Medical devices including medicaments and methods of making and using same

ABSTRACT

The present invention recognizes that medical devices, such as but not limited to contact lenses, can be made having a coating made at least in part using printing technologies to provide drug storage and drug release structures. The coating preferably includes at least one drug reservoir layer and a least one barrier layer, and can include structures, such as but not limited to capillary structures, which alone or in combination modulate the release of the drug from the coating. One aspect of the present invention is a medical device that incorporates a drug in at least one coating. A second aspect of the present invention is a method of making a medical device that incorporates a drug in at least one coating. A third aspect of the present invention is a method of using a medical device of the present invention to treat or prevent a disease, disorder or condition.

The present application is a Divisional Application of U.S. Ser. No.15/891,456, filed Feb. 8, 2018, entitled, “Contact Lenses IncludingMedicaments and Methods of Making and Using Same;” which is a DivisionalApplication of U.S. Ser. No. 13/065,904, filed Apr. 2, 2011, entitled“Contact Lenses Including Medicaments and Methods of Making and UsingSame;” which claims benefit of priority to U.S. Provisional applicationSer. No. 61/341,824, filed Apr. 3, 2010, entitled “Contact LensesIncluding Medicaments and Methods of Making and Using Same;” each ofwhich is incorporated by reference in its entirety herein.

TECHNICAL FIELD

The present invention generally relates generally to the fields ofmedical devices, including but not limited to contact lenses, thatinclude a medicament or drug in a coating layer and methods of makingand using such medical devices. The coating layer is preferably made atleast in part using printing, preferably but not limited to digitalprinting.

BACKGROUND

Medical devices that include a medicament have been known. Examplesinclude contact lenses and stents for the treatment or prevention of avariety of diseases, disorders or conditions, such as contact lenses forthe treatment of glaucoma and stents for the treatment or prevention ofrestenosis. Existing medical devices that include medicaments aretraditionally made using relatively simple drug coating or drugimpregnation technologies that do not allow the modulated release of themedicament from the coating. The present invention addresses theselimitations and provides additional benefits as well.

A variety of medical devices, particularly contact lenses, that includea medicament have been described. For example, U.S. Pat. No. 7,638,137B2to Chuahan et al. describes drug delivery systems through dispersion oftransparently encapsulated drugs within the lens. However, suchdispersion inside the lens could alter the physical properties of thepolymeric lens materials. Also, while encapsulated drugs may be visuallytransparent in certain instances, the may interfere with the opticalproperties of the lens. Also, drugs inside the lens may be released fromeither or both the anterior and posterior surfaces of the lens and thusnot providing the desired dosage of a drug to the cornea or other areasof an eye structure and surrounding tissues. This document also providesa survey of the literature relating to issues relating to drug release.

U.S. published Patent Application No. 2009/07504245A1 to Orilla et al.describe the masking of a color of a drug by applying a color layer ontop of the drug. This document does not relate to the controlling thedrug release rate from the lens.

Also, U.S. published Patent Application No. 2009/0004244 to Burke et al.describes deposing a drug in an iris simulated pattern to provide acosmetic appearance of a lens for drug delivery. This document does notrelate to how drug release rate can be controlled.

In addition, U.S. Pat. No. 6,887,858 to Yerxa describes formulations forthe treatment of dry eye diseases. The document is not related to drugrelease from a medical device such as a contact lens.

Furthermore, U.S. Pat. No. 6,294,553 to Gil et al. describes a drug forocular surface pain. Gil et al. does not, however relate to controlleddrug delivery rate.

U.S. Pat. No. 3,786,812 to Neefe describes the use of contact lenses fordrug delivery. This document, however, does not relate to achievingdesired release rate of a drug from a lens.

Also, U.S. Pat. Nos. 3,618,604 and 3,828,777 describe polymeric plasticsin which a drug is held to provide controlled drug release rate. Thedocuments, however, do not relate to the ability to adjust drug releaserate.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts a step-by-step construction of a 3D structure on surfaceof a medical device such as but not limited to a contact lens. Thesesteps include constructing one or more drug reservoir layer, barrierlayers of different diffusivity along with capillaries of differentheights. All these structures are created to obtain a desirable drugrelease rate.

FIG. 2 depicts different types of 3D structures built on the surface ofa medical device such as but not limited to a contact lens to obtain adesirable drug release rate.

FIG. 3 also depicts different types of 3D structures built on thesurface of a medical device such as but not limited to a contact lens toobtain a desirable drug release rate.

FIG. 4 depicts a further extension of capillaries and barrier layers toaccommodate one or more drugs or to obtain a desirable drug releaserate. The drug reservoir layer can be built on the surface of themedical device such as but not limited to a contact lens.

FIG. 5 depicts the application of a drug receiving layer on the surfaceof a medical device such as but not limited to a contact lens byprinting.

FIG. 6 depicts one aspect of the invention where the drug is one of theingredients of printable formulation that also includes monomers withderivatized oligomers.

FIG. 7 depicts one aspect of the invention where there is auni-directional or near uni-directional release of a drug from themedical device such as but not limited to a contact lens utilizing ablocking layer that prevents release of a drug in one direction.

FIG. 8 depicts one aspect of the invention where it is desirable toprovide two or more different drugs, such as but not limited to one forglaucoma and another for comfort enhancement of a medical device such asbut not limited to contact lenses such as but not limited to for dry eyeat the same time or at different times. This figure depicts the use ofconcentric layers of two drugs whereas FIG. 4 depicts the use ofproviding separate layers of drugs at different heights and thicknessesof a drug reservoir layer to achieve this function and related structurefor release of two different drugs at the same time or at differenttimes.

FIG. 9 also depicts one aspect of the invention where there is auni-directional or near uni-directional release of a drug from themedical device such as but not limited to a contact lens utilizing ablocking layer that prevents release of a drug in one direction.

FIG. 10 depicts structures of the present invention where layers of atleast one barrier layer are provided above one another over at least onedrug reservoir layer. The rate of diffusion of a drug from the at leastof drug reservoir layer through the three barrier layers A, B, and C canbe expressed as Rate=R_(a)×R_(b)×R_(c).

FIG. 11 depicts structures of the present invention where layers of atleast one barrier layer are provided along side one another over atleast one drug reservoir layer. The rate of diffusion of a drug from theat least of drug reservoir layer through the three barrier layers A, B,and C can be expressed as Rate=R_(a)+R_(b)+R_(c), where R_(a), R_(b) andR_(c) represent drug release rates through materials through materialsA, B, and C, respectively, and are related to thickness and otherphysical and chemical properties of the material.

FIG. 12 depicts structures of the present invention where layers of atleast one barrier layer are provided along side one another over atleast one drug reservoir layer and provide capillary structures inbetween them. The rate of diffusion of a drug from the at least of drugreservoir layer through the three barrier layers A, B, and C can beexpressed as Rate=R_(a)+R_(b)+R_(c)+R_(capillary).

SUMMARY

The present invention recognizes that medical devices, such as but notlimited to contact lenses, can be made having at least one coating layermade at least in part using printing technologies to provide drugstorage and drug release structures. The at least one coating layerpreferably includes at least one drug reservoir layer and a least onebarrier layer, and can include structures, such as but not limited tocapillary structures, which alone or in combination modulate the releaseof the drug from the coating.

A first aspect of the present invention is a medical device thatincorporates at least one drug in at least one coating, where the atleast one coating includes at least one drug reservoir layer and atleast one barrier layer.

A second aspect of the present invention is a method of making a medicaldevice that incorporates at least one drug in at least one coating,where the at least one coating includes at least one drug reservoirlayer and at least one barrier layer.

A third aspect of the present invention is a method of using a medicaldevice of the present invention to treat or prevent a disease, disorderor condition.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Generally, the nomenclatureused herein and the laboratory procedures well known and commonlyemployed in the art. Conventional methods are used for these procedures,such as those provided in the art and various general references such asU.S. Pat. Nos. 5,160,463; 5,271,874; 5,018,849; 5,034,166; 5,414,477;6,315,410; 6,899,426B2; 7,638,137B2; US Published Patent ApplicationUS2009/0062381A1; Day et al., Current Optometric Information andTerminology, Third Edition, American Optometric Association (1980);Howley's Condensed Chemical Dictionary (1981); Federation of Societiesfor Coatings Technology; and “Contact Lenses for Drug Delivery:Achieving Sustained Release with Novel Systems,” Alvarez Lorenzo et. al.American Journal of Drug Delivery, (2006) 4 (3) (3) (5). Where a term isprovided in the singular, the inventors also contemplate the plural ofthat term. The nomenclature used herein and the laboratory proceduresdescribed below are those well known and commonly employed in the art.As employed throughout the disclosure, the following terms, unlessotherwise indicated, shall be understood to have the following meanings:

“Directly” refers to direct causation of a process that does not requireintermediate steps.

“Indirectly” refers to indirect causation that requires intermediatesteps.

“Digitally Encoded Image” or “Digital Image” refers to an image that hasbeen created or stored in a digital format. A digitally encoded imagecan be made using methods known in the art, such as artistic renditionsor scanning or otherwise translating an image. A digitally encoded imagecan be stored on appropriate storage medium, such as magnetic medium orpolymers such as cyclo-olefin copolymers. A plurality of digitallyencoded images can be stored together or separately to form a databaseof digitally encoded images that are accessible individually or incombination. Such digitally encoded images can be altered usingestablished methods, such as artistic renditions or image modulatingsoftware. A plurality of images can also be merged to form a newdigitally encoded image.

“Solvent” refers to an aqueous, organic or inorganic solvent, such aswater, isopropanol, tetrahydrofuran or acetone.

“Surfactant” refers to a surfactant as that term is known in the art,such as, for example, acetylene glycol or polyoxyethylene alkyl.

“Dispersant” refers to dispersants as they are known in the art, suchas, for example, the Tergitol series from Union Carbide, polyoxylatedalkyl ethers, alkyl diamino quaternary salts or “Pecegal “O” from GAF(U.S. Pat. No. 5,560,766). Dispersants are preferably used at betweenabout 0.1% and about 10%, more preferably between about 0.5% and about5%.

“Lens” as used herein refers to a composition of matter that cantransmit light. A lens preferably can act as an optical lens, such as acontact lens. In certain aspects of the present invention, a lens neednot act as an optical lens, such as a contact lens that is used fortherapeutic purposes as opposed to purposes relating to the correction,improvement or alteration of a user's eyesight.

“Contact Lens” refers to a structure that can be placed on or within awearer's eye. A contact lens can correct, improve, or alter a user'seyesight, but that need not be the case. A contact lens can be of anyappropriate material known in the art or later developed, and can be asoft lens, a hard lens or a hybrid lens. A contact lens can be in a drystate or a wet state.

“Soft Lens” refers to a variety of soft lenses as they are known in theart that are characterized as having, for example, at least one of thefollowing characteristics: oxygen permeable, hydrophilic or pliable.

“Hard Lens” refers to a variety of hard lenses as they are known in theart that are characterized as having, for example, at least one of thefollowing characteristics: hydrophobic, gas permeable or rigid.

“Hybrid Lens” refers to a variety of hybrid lenses as they are known inthe art, such as, for example, a lens having a soft skirt and a hardcenter.

“Dry State” refers to an article of manufacture or a portion thereof ina state prior to hydration or the state of an article of manufacture ora portion thereof under storage or use conditions.

“Wet State” refers to an article of manufacture or a portion thereof ina hydrated state.

“Transparent” refers to a substantial portion of visible lighttransmitted through a structure, such as greater than or equal to 90% ofincident light.

“Opaque” refers to a substantial portion of visible light reflected orabsorbed by a structure, such as greater than or equal to 90% ofincident light.

“Partially opaque” refers to a combination of transparent and opaque.

“Hydrogel” refers to a polymer that swells in an aqueous solution due tothe absorbance of water. A hydrogel includes water or an aqueoussolution as part of its structure.

“Polymer” refers to a linkage of monomers. Preferably, a polymer is apolymer appropriate for use in lenses, such as contact lenses. A polymercan be, for example, a homopolymer, a heteropolymer, a copolymer, ahydrophobic polymer, a hydrophilic polymer or any combination thereof.

“Hydrophobic Polymer” refers to a polymer that does not absorb anappreciable amount of water or an aqueous solution (see, U.S. Pat. No.5,034,166).

“Hydrophilic Polymer” refers to a polymer that absorbs an appreciableamount of water or an aqueous solution (see, U.S. Pat. No. 5,034,166).Lens forming materials that are suitable in the fabrication of contactlenses are illustrated by one or more of the following U.S. Pat. Nos.2,976,576; 3,220,960; 3,937,680; 3,948,871; 3,949,021; 3,983,083;3,988,274; 4,018,853; 3,875,211; 3,503,942; 3,532,679; 3,621,079;3,639,524; 3,700,761; 3,721,657; 3,758,448; 3,772,235; 3,786,034;3,803,093; 3,816,571; 3,940,207; 3,431,046; 3,542,461; 4,055,378;4,064,086; 4,062,624; and 5,034,166.

“Hydrophilic Monomer” refers to monomers used to make soft lenses, suchas hydroxyethylmethacrylate, methacrylic acid, or N-vinylpyrrolidone(U.S. Pat. Nos. 5,271,874; 5,272,010).

“Hydrophilic Monomer” refers to monomers used to make hard lenses, suchas methylmethacrylate, ethoxyethylmethacrylate, styrene, or silicone(U.S. Pat. No. 5,271,874; 5,272,010).

“Homopolymer” refers to a polymer comprising a single type of monomersuch as hydroxyethylmethacrylate.

“Heteropolymer” refers to a polymer comprising more than one type ofmonomer such as hydroxyethylmethacrylate and methacrylic acid.

“Copolymer” refers to the use of two different polymers to make apolymer chain.

“Acrylic Polymer” or “Acrylics” refers to a variety of polymer of thatgenus and species as they are known in the art, such as, for example,hydroxyethylmethacrylate.

“Silicone Polymer” or “Silicones” refers to a variety of polymers ofthat genus and species as they are known in the art, such as, forexample Tris (such as Tris(pentamethyldisiloxyanyl)-3-methacrylate-propylsilane or3-methacryloxypropy tris(trimethylsiloxy)silane).

“Polycarbonate Polymer” or “Polycarbonate” refers to a variety ofpolymers of that genus and species as they are known in the art, suchas, for example Lexan.

“Initiator” in the context of polymerization refers to an initiator asthat term is known in the art, such as, for example, a chemical thatstarts a polymerization reaction.

“UV Initiator” in the context of polymerization refers to a UV initiatoras that term is known in the art, such as, for example, a chemical thatbecomes reactive or active with the adsorption of energy, such as UVenergy, such as, for example benzoin methyl ether.

“Binder” or “bonding agent” refers to compounds used perform thefunction of increasing the interaction between moieties, such as betweenmonomers and polymers such as those terms are known in the art. Examplesof binders or binding agents are hexamethylene diisocyanate or otherisocyanate compounds.

“Thickener” refers to a compound that is used to increase the viscosityof a liquid or partially liquid mixture or solution such as that term isknown in the art. An example of a thickener is polyvinyl alcohols.

“Anti-kogating agent” or “non-kogating agent” refers to compounds thatfacilitate printing processes that utilize nozzles, such as such termsare known in the art.

“Dispersant” refers to a surface-active agent added to a suspendingmedium to promote the distribution and separation of fine or extremelyfine solid particles.

“Thermal Initiator” in the context of polymerization refers to a thermalinitiator as that term is known in the art, such as, for example, achemical that becomes active or reactive with the absorption of heatenergy, such as, for example, Vazo-64 or azobisisobutyronitrile.

“Anti-Bacterial Agent” refers to a compound or composition that can actas a bactericidal or bacteriostatic or can reduce the growth rate of abacteria such as tetrabutylammonium chloride.

“Anti-Fungal Agent” refers to a compound or composition that can act asa fungicidal or fungistatic or can reduce the growth rate of a fungisuch as benzalkonium chloride salicylic acid.

“Disinfectant” refers to a compound or composition that can reduce thetype, number or diversity of microorganisms.

“Humectant” refers to compounds that reduce evaporation, such asethylene glycol.

“Printing” refers to the application of at least one printingformulation to a surface or structure. Printing can use any appropriatedevice or method known in the art of later developed for a particularpurpose.

“Printing Device” refers to any appropriate device for printing on asurface or structure known in the art or later developed for aparticular purpose. Preferably, a printing device includes thedispensation of microdroplets of liquid. The size or volume of themicrodroplets can vary, but generally the smaller the microdroplet, thehigher the quality of the printing produced. Preferred microdroplets arebetween about 1 picoliter and about 1,000 microliters, preferablybetween about 10 picoliters and about 10 microliters or between about100 picoliters and about 1 microliter. Preferred microdroplets can alsobe in the microliter range.

“Ink Jet Printing” refers to printing using a printing device thatcomprises at least one ink jet. Such printing devices are commerciallyavailable such as through, for example, Hewlett Packard Corporation(such as DeskJet 560C printer cartridges) and Encad Corporation.

“Piezo Printing” refers to printing using a printing device thatcomprises at least one piezo printing structure. Such piezo printingstructures are known in the art, such as, for example, those availablethrough Packard Instruments and Hewlett Packard Corporation or CanonInc.

“Thermal Printing” refers to printing using a printing device thatcomprises at least one thermal printing structure. Such thermal printingstructures are known in the art, such as, for example, those availablethrough Hewlett Packard Corporation.

“Laser Printing” refers to printing using a printing device that uses atleast one laser printing structure. Such printing structures are knownin the art, such as, for example, those available through Cannon orHewlett Packard Corporation.

“Pad Transfer Printing” refers to printing using a pad transfer printingdevice. Such pad transfer printing devices are known in the art,particularly for printing in the field of contact lenses. Briefly, alayer is placed or printed on a pad transfer device and the layer on thepad transfer device is transferred to another surface, such as a polymeror lens or other surface (U.S. Pat. No. 3,536,386 to Spivack, issuedOct. 27, 1970; U.S. Pat. No. 4,582,402 to Knapp, issued Apr. 15, 1986;U.S. Pat. No. 4,704,017 to Knapp, issued Nov. 3, 1987; U.S. Pat. No.5,034,166 to Rawlings et al., Jul. 23, 1991; U.S. Pat. No. 5,106,182 toBriggs et al., issued Apr. 21, 1992; U.S. Pat. No. 5,352,245 to Su etal., issued Oct. 4, 1994; U.S. Pat. No. 5,452,658 to Shell, issued Sep.26, 1995 and U.S. Pat. No. 5,637,265 to Misciagno et al., issued Jun.10, 1997).

“Impregnation” refers to a drug being contacted with a surface, such asa polymer, and the drug diffuses into the polymer (EP 0357062 toPfortner, published Mar. 7, 1990).

“Chemical Bond” refers to a covalent bond or non-covalent bond.

“Polymer-Polymer Bond” refers to two polymers forming covalent ornon-covalent bonds, such as by cross linking polymers formed between twopolymers, such as hydroxyethyl methylacrylate andehtyleneglycoldimethacrylate.

“Dry State” refers to a polymer that is not fully hydrated.

“Wet State” refers to a polymer that is fully hydrated.

“Forming a Lens” or “Fabricating a Lens” refers to any method orstructure known in the art or later developed used to form a lens. Suchforming can take place, for example, using cast-molding, spin-casting,cutting, grinding, laser cutting, stamping, trimming, engraving, etchingor the like (U.S. Pat. No. 4,558,931 to Fuhrman, issued Dec. 17, 1985).

“Cast-Molding” in the context of forming a lens refers to the formationof at least a portion lens using a mold (U.S. Pat. No. 3,536,386 toSpivak, issued Oct. 27, 1970; U.S. Pat. No. 3,712,718 to LeGrand et al.,issued Jan. 23, 1973; U.S. Pat. No. 4,582,402 to Knapp, issued Apr. 15,1986; U.S. Pat. No. 4,704,017 to Knapp, issued Nov. 3, 1987; U.S. Pat.No. 5,106,182 to Briggs et al., issued Apr. 21, 1992; U.S. Pat. No.5,160,463 to Evans et al., issued Nov. 3, 1992; U.S. Pat. No. 5,271,874to Osipo et al., issued Dec. 21, 1993 and EP 0357062 to Pfortner,published Mar. 7, 1990)

“Spin-Casting” in the context of forming a lens refers to the formationof a lens using centrifugal force (U.S. Pat. No. 3,557,261 to Wichterle,issued Jan. 19, 1971 and U.S. Pat. No. 5,034,166 to Rawlings et al.,issued Jul. 23, 1991).

“Information Storage Medium” refers to any medium of expression that canstore information in any appropriate format either permanently ortransiently. Preferred information storage medium includes paper,electronic medium, magnetic medium or polymers, such as cyclo-olefincopolymers.

“Electronic Medium” refers to information storage medium that can storeinformation in electronic form. For example, electronic medium includesmagnetic storage medium, such as diskettes.

“Machine Readable Format” refers to information stored on or within aninformation storage medium in a form, language or arrangement such thata machine, such as a central processing unit (CPU) can access and usethe information.

“Database” refers to a collection of information, such as digitalimages. The information is preferably provided on or within aninformation storage medium and can be separate from or integral with acentral processing unit.

“Printable formulation” refers to a printable formulation that can beused in conjunction with a printing technology or printing device toprovide at least one structure, at least one layer, or a combinationthereof, of the present invention.

“Subject” refers to, but is not limited to, a human or non-humanprimate; a companion animal such as but not limited to a dog, a cat, abird, a fish, a reptile, an amphibian, a fox, a wolf, a pig, a horse orother companion as is known in the art; laboratory animal, such as, butnot limited to a mouse, a rat, a guinea pig, a rabbit, a dog, a cat, aferret, a pig, or other laboratory animals as is known in the art;working animals such as but not limited to a dog, a horse or otherworking animals as are known in the art; or any other animal as in knownin the art that may be in need of the technology of the presentinvention or for testing of the technology of the present invention.

“Digital printing” refers to the printing of at least a portion of alayer of the present invention using at least one digital image printingtechnology.

“3D printing” or “three dimensional pringint” refers to the printing ofthree-dimensional structures using appropriate printing technologies andprinters as are known in the art or later developed. 3D printing isuseful in the making of parts, products or layers using acomputer-driven, additive process, one or more layers at a time. 3Dprinting can build parts or other structures such as layers, using anyappropriate material, such as, but not limited to plastic or metal,directly from CAD drawings or other digital images that have beenpreferably cross sectioned into may, if not hundreds or thousands oflayers. 3D printing provides a faster and less costly alternative tomachining, such as but not limited to machining, including but notlimited to cutting, turning, grinding and drilling of materials, such assolid materials. Although various techniques are used in 3D printing inthe relevant art, 3D printers use method of additive fabrication, thatis the building a part or structure one layer at a time, with layersranging in thickness from about a millimeter to less than 1/1,000 of aninch. The building material can be in any appropriate form, such as, butnot limited to a liquid, a power or a sheet of material that is cured byheat, UV light, a chemical reaction or other appropriate method.

Other technical terms used herein have their ordinary meaning in the artthat they are used, as exemplified by a variety of technicaldictionaries.

Introduction

The present invention recognizes that medical devices, such as but notlimited to contact lenses, can be made having at least one coating madeat least in part using printing technologies to provide drug storage anddrug release structures. The coating preferably includes at least onedrug reservoir layer including at least one drug, and a least onebarrier layer. The at least one barrier layer can include structures,such as but not limited to capillary structures, that alone or incombination, modulate the release of the drug from the coating.

As a non-limiting introduction to the breath of the present invention,the present invention includes several general and useful aspects,including:

1) A medical device that incorporates a drug. The medical deviceincludes a coating that includes at least one drug reservoir layer thatincludes a drug and at least one barrier layer.

2) A method of making a medical device that incorporates a drug. Themedical device includes a coating that includes at least one drugreservoir layer that includes a drug and at least one barrier layer. Thecoating is made at least in part using printing.

3) A method of using a medical device of the present invention to treator prevent a disease, disorder or condition. The medical device can beimplantable or non-implantable and is placed at a location in a subjectappropriate for treating or preventing a disease, disorder or condition.

These aspects of the invention, as well as others described herein, canbe achieved by using the methods, articles of manufacture andcompositions of matter described herein. To gain a full appreciation ofthe scope of the present invention, it will be further recognized thatvarious aspects of the present invention can be combined to makedesirable embodiments of the invention.

I Medical Devices Including a Medicament

The present invention includes an article of manufacture that includes:a) a medical device including at least one surface; and b) one or morecoatings provided on at least a portion of the at least one surface. Thecoating includes: 1) at least one drug reservoir layer produced at leastin part by printing, wherein the at least one drug reservoir layerincludes at least one drug; and 2) at least one barrier layer includingone or more structures produced at least in part by printing. The atleast one barrier layer modulates the release of the at least one drugfrom the at least one drug reservoir layer (see, for example, FIG. 2 andFIG. 3).

Medical Device

The medical device of the present invention can be any known in the artor later developed. The medical device can be implanted within a subjectas is the case with many medical devices as they are known in the artsuch as, for example, cardiac stents, joint replacements such a hip andknee among others, birth control sticks, pacemakers, breast implants,facial implants for reconstructive or cosmetic purposes such as for thecheeks and chin, intrauterine devices (IUD's), pins and mesh andresorbable materials such as known in the art (such as, but not limitedto, polylactic acid (PLA)) for bone reconstruction or immobilization,dental implants, filters to entrap blood clots in blood vessels, opticallens replacements for cataract treatment, voice boxes for throat cancerpatients and the like.

The medical device of the present invention can also be non-implantableas they are know in the art, such as, for example, contact lenses,dental apparatus, drug patches, transdermal drug patches including butnot limited to birth control, Alzheimer's patches, smoking cessationpatches, hearing aids, earplugs or other devices inserted into the earto treat swimmer's ear and ear infections and the like.

The medical device of the present invention can be made of anyappropriate material or combination of materials as appropriate for thepurpose and location where the medical device will ultimately residewithin or on a subject. The choice of materials for the medical deviceis determinable by one skilled in the art, and there are numerousexamples in the prior art for the skilled artisan to follow. For thepresent invention, it is generally the surface of the medical device onwhich a coating is provided, but this need not be an exclusiverequirement.

Surface

The surface of a medical device that is to be coated in the manner ofthe present invention can be of any appropriate material and is usuallydetermined or influenced by the nature of the medical device and where,and how long, it is to be implanted, or not implanted, within or on asubject.

Many medical devices present metal on their surface. Examples include,but are not limited to, bone pins and mesh for bone repair andstabilization. Metals that can be used as a surface include, forexample, steal, stainless steel, gold, silver and the like.

Some medical devices present a plastic or polymer on their surface.Examples include but are not limited to contact lenses, IUD's animplantable birth control sticks. There are a wide variety of polymersand plastics available for use in medical devices, which are toonumerous to enumerate here. Individual polymers and plastics arediscussed further herein, and are intended as a limiting list of suchmaterials.

Other medical devices present partially polymerized polymers duringtheir manufacture, but not necessarily in the final product. Thepartially polymerized polymers can be used as an intermediate product tofacilitate bonding with other components of the device. Examplesinclude, but are not limited to, contact lenses and the like.

Still other medical devices present on their surface polymer matrices.Examples include, but are not limited to, limited to materials thatallow for skin or other tissue regenerations, such as for trauma,disease, disorder, condition such as, for example, burn treatment, suchas those that contain fibronectin or other structural proteins. Thepolymer matrix or protein matrix can be any appropriate, such as but notlimited to proteins, nucleic acids, and carbohydrates.

In addition, still other medical devices present on their surfacesilicone, ceramic, glass, carbon (inclusive of nanotubles and graphite)and fabric. Examples include, but are not limited to, breast implants,penal implants, hip replacement parts, knee replacement parts, bandagesfor burn and trauma wounds, and the like. The silicone, ceramic, glass,carbon (including but not limited to graphite including sheets, carbonnano-structures such as tubes, balls, sheets and other structures) andfabric can be any appropriate and as are realized in the art.

The surface of a medical device can also be pretreated or modified byvarious processes to, in some instances, clean or otherwise prepare thesurface for receiving the coating of the present invention. Somepretreatments may be physical in nature, such as polishing, scarring orscoring, whereas others may be chemical in nature. Preferred chemicalprocess include, but are not limited to, chemical coating, chemicalcleaning, chemical texture modification, chemical or electrochemicalactivation or creation of reactive groups on or within said at least onesurface, application of one or more chemicals to said at least onesurface, and combinations thereof.

Drug Reservoir Layer

The drug reservoir layer serves to store a drug for later release fromthe coating. The drug reservoir layer is preferably porous or otherwiseis able to contain a drug for this purpose. In one aspect of the presentinvention, the drug reservoir layer is solid or semi-solid, such as agel or sol, which can reversibly entrap a drug for later release. Thedrug reservoir layer can be provided first without a drug and the drugadded at a later step (see, FIG. 5). In the alternative the drugreservoir layer can be provided with a drug in one step (see, FIG. 6).The drug reservoir layer is preferably made using printing technology.The choice of polymer depends on several factors, including, forexample, the printing technology to be used to print the drug reservoirlayer.

The drug reservoir layer can include a polymer with the characteristicsstated above. Preferable polymers include, but are not limited to,polyHEMA, polyGMA, polyvinylalcohol, polyDMA, PMMA(polymethylacrylicacid), polycarbonate, PVP (polyvinylpyrolidone),siloxane, and the like. Depending on the polymer and the printingtechnology chosen, the polymer can be provided in a monomer state andlater polymerized, or in the alternative, provided in a partiallypolymerized state.

The drug reservoir layer can also include a partially polymerizedpolymer with the characteristics stated above and can be any asappropriate. Preferable polymers include, but are not limited topolyHEMA, polyGMA, polyvinylalcohol, polyDMA, PMMA(polymethylacrylicacid), polycarbonate, PVP (polyvinylpyrolidone),siloxane, and the like. Depending on the partially polymerized polymerand the printing technology chosen, the partially polymerized polymercan be provided in a monomer state and later partially polymerized, orin the alternative, provided in a partially polymerized state.

The drug reservoir layer can include a polymer matrix with thecharacteristics stated above and can be any as appropriate. Preferablepolymer matrix include, but are not limited to, proteins, nucleic acids,and carbohydrates. Depending on the polymer and the printing technologychosen, the polymer matrix can be provided in a monomer state and laterpolymerized, or in the alternative, provided in a polymerized state.

In addition, still other materials can be used for the drug reservoirlayer, such as, but not limited to silicone, ceramic, glass, carbon(inclusive of nanotubles and graphite) and fabric. The silicone,ceramic, glass, carbon and fabric can be any appropriate and as arerealized in the art and the choice generally relates, as with othermaterials used in the drug reservoir layer, to they physicalcharacteristics such as the ability to accept and retain a drug forlater release and the printing technology chosen to print the drugreservoir layer.

Preferable materials for the drug reservoir layer include derivatizedoligomers. Preferable derivatized oligomers include, but are not limitedto HEMA (mydroxyethylmethylacrylates), DMA (dimethylacrylamides), GMA(glycidolmethylacylates), PVA (polyvinlyalcohols), silicone or siloxane.As with other materials used, the choice of derivatized oligomersdepends on the physical characteristics of the material and the printingtechnology used to make the drug reservoir layer.

If the material used for the drug reservoir layer need to be polymerizedand cured, then a polymerization initiator or curing initiator needs tobe used. The requirement for a polymerization initiator or curinginitiator depends on the particular type of polymer/monomer beingutilized and the choice is established in the technology. Preferablepolymerization initiator or curing initiators include, but are notlimited to at least one of UV cure, thermal cure, room temperature cure,simultaneous printing and UV curing or e-beam.

As set forth in the figures, the drug reservoir layer can release a drugin one or more directions. For example, turning to a contact lens, thedrug receiving layer can release drug towards the cornea or towards theeyelid when the contact lens is engaged with the eye. The use of barrierlayers, or lack thereof, allows for the design of structures that allowdrug to be released in one or both directions.

The material used for the drug receiving layer can be bonded to,permanently bonded to, or not bonded to the surface. Certain materialsthat can be used for the drug reservoir layer inherently bond or do notbond to a surface, depending on the nature of the surface. As discussedpreviously, the surface can be modified, such as through chemicalmedication or other methods or techniques, to allow the drug reservoirlayer to chemically bond or react with the drug receiving layercomponents.

Drug Receiving Layer

The manufacture of the drug reservoir layer can include the use of adrug receiving layer. In this instance, a drug receiving layer isapplied to the surface by an appropriate means or method, such asprinting. The drug receiving layer could include or not include a drugat this juncture in time. The drug receiving layer has physical andchemical characteristics to allow the efficient and localized acceptanceof a drug applied thereto using appropriate methods, preferablyprinting. Once the drug receiving layer is applied to the surface, thena drug, or an additional drug, is applied thereto to entrap the drug oradditional drug therein for later release.

The drug receiving layer can be of any appropriate material with theappropriate physical and chemical characteristics to obtain a structurewith the desired characteristics discussed herein. The drug receivinglayer can be a chemical. Preferred materials for the drug receivinglayer include, but are not limited to, a highly absorbent polymer suchas, but not limited to, a polyvinlylpyrrolidone homopolymer, apolyvinylpyrrolidone copolymer, a polyacrylamide homopolymer, apolyacrylamide copolymer, a polyacrylate homopolymer, a polyacrylatecopolymer, a proteinaceous material, a carbohydrate, or a combinationthereof.

As there may be other layers applied to the surface prior to the drugreceiving layer, the drug receiving layer can be applied to such priorlayers using appropriate methods. As with other layers of the coating ofthe present invention, the drug receiving layer can be provided by anyappropriate method, preferably by printing technology.

Where the drug receiving layer includes a polymer, then the drugreceiving layer can include a bonding agent or crosslinking agent inorder to aid in entrapping or otherwise immobilizing a drug for laterrelease from the drug reservoir layer. Preferable bonding agentsinclude, but are not limited to methylacrylic acid, titanates, andsilanes. Preferable crosslinking agents include, but are not limited toHDI, and devivitized oligomers of HEMA, GMA, DMA and PVA, PolyfunctionalAziridine, and multifunctional carbodimide.

In one preferred aspect of the present invention, the drug receivinglayer includes a highly absorbent polymer. Preferred highly absorbentpolymers include, but are not limited to a polyvinylpyrrolidinehomopolymer, a polyvinylpyrrolidone copolymer, a polyacrylamidehomopolymer, a polyacrylamide copolymer, a polyacrylate homopolymer, apolyacrylate copolymer, a proteinaceous material, a carbohydrate, or acombination thereof.

The preferred method of application of a drug receiving layer of thepresent invention is printing technologies and coating technologies.Preferable methods of printing include, but are not limited to directcoating, application of droplets or microdroplets, ink jet printing,soaking, impregnation, spin coating, drip coating, screen coating, silkscreen coating, or pad printing such as those methods are know in theart.

Drug

The drug provided in the drug reservoir agent is a matter of choice toone skilled in the appropriate arts depending on the disease, disorderor condition to be treated or prevented, along with the location of thearticle of manufacture on or with the subject and the nature of themedical device used. For example, drug for the treatment or preventionof glaucoma would be provided with a contact lens, whereas a drug forthe treatment or prevention of restinosis would be provided with astent.

The drug released from the article of manufacture should be of theappropriate amount, duration and dosing in order to be an effectiveamount to prevent or treat at least one disease, disorder or condition.The amount, duration and dosing of a drug to a particular location forsuch treatment or prevention is available to one skilled in the art. Thepresent invention allows localized and controlled dosing in terms of theamount and duration of the dose and can allow for the continuous orintermittent release of drug for a regime of drug delivery.

One preferable aspect of the present invention is the delivery of a drugto the eye to treat or prevent or treat diseases, conditions ordisorders of the eye. There are drugs known to treat or prevent avariety of diseases and conditions with appropriate regimes of dose,time course of administration, and route of administration. The presentinvention allows for varying the regime of dose and time course andprovides a highly localized route of administration as well. Preferreddrugs that are antibiotics useful for treatment of eye infectionsinclude, but are not limited to, gentamicin, tobramycin, erythromycin,polytrim, cirproflizacin, viamox, and xymar. Preferred drugs that areused to treat glaucoma include, but are not limited to, timolol,alphagan, axopt, cosopt, lumigan, travatan, xalatan, and combigan.Preferred drugs that are ani-inflammatory that are used to treatdiseases, disorders and conditions of the eye include, but are notlimited to, perdforte, lotemax, fluromethlone, nevanac, acular andxibrom. Other drugs known in the art to treat or prevent diseases,conditions or disorders of the eye include, but are not limited topilocarpine, dexamethasone, pilocarpine nitrate, tropicamide, timolol,timolol nitrate, timolol maleate, methyl prednisolone, flurbiprofen,penicillin G, gentamicin, ciprofloxacin, tobramycin, sulphacetamindesodium, indomethacin, hydrocortisone, indomethacin, pilocarpinehydrochloride, ciprofloxacin hydrochloride,insulin, indomethacin, andketorolac tromethamine, either alone or in combination. (see, forexample, Yasmin Sultana, Rahul Jain, Rahul Rathod, Asgar Ali, M. Aqil,Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University,New Delhi 110062, INDIA. “Advances in Ophthalmic Drug Delivery Systems:Part I” By—Apr. 12, 2005, in Latest Reviews Vol. 3 Issue 2, 2005,www.pharmmainfo.net/reviews/advances-opthalmic-drug-delivery-systems-part-i,and Yasmin Sultana, Rahul Jain, Rahul Rathod, Asgar Ali, M. Aqil,Department of Pharmaceutics, Faculty of Pharmacy, Hamdard University,New Delhi 110062, INDIA, “Advances in Ophthalmic Drug Delivery Systems:Part II” By—Apr. 12, 2005, in Latest Reviews Vol. 3 Issue 2, 2005,www.pharmmainfo.net/reviews/advances-opthalmic-drug-delivery-systems-part-ii(Apr. 1, 2011) (“Sultana et al. Part II). Sultana et al. Part I andSultana et al. Part II provide reviews and listings of drugs ancombinations thereof to treat or prevent various diseases, conditionsand disorders of the eye. The patent literature also provides for oculardrug delivery devices and strategies as provided by Sultana et al. PartI and Sultana et al. Part II. See, for example US patent and USpublished patent application numbers: U.S. Pat. Nos. 4,925,581;5,227,372; 5,296,228; 5,480,914; 5,578,638; 5,705,194; 5,888,493;6,242,442; 6,297,240; 6,316,441; 6,410,045; 6,416,740; 20020071874;20020197300; 20030017199; 5,837,226; 6,017,875; 6,154,671; 6,217,896;6,319,240; 6,335,335; 6,410,045; 6,539,251; 6,579,519; 20020026176;20030147849; 20020064513; 20020114778; 20020119941; 20020197300;20030175324; 20030185892; 20030191426; and 20040037889.

In one aspect the present invention, the drug is provided in the drugreservoir layer and released from the drug receiving either alone or incombination with other ingredients. Alternatively, the drug can beprovided in the drug reservoir layer with such other ingredients andthen released from the drug reservoir layer without such otheringredients. In a preferred aspect of the present invention the drug isprovided at least in part as a sole active ingredient without any otheringredient association that can alter the activity or deliverability ofthe at least one drug. That is to say that the drug is provided orreleased alone and free of other ingredients, such as but not limited tothose used for encapsulation, micro-encapsulation or emulsification of adrug.

The drug can be provided or released from the drug receiving layer andcoating of the present invention in an encapsulated form. Encapsulationof drugs is known in the art, such as and is within the skill of theordinary artisan. Preferred encapsulation materials include, but are notlimited to: biodegradable polycyanoacrylate, biodegradablepoly(alkylcyanoacrylates), biodegradable calcium phosphate, legumin,polysaccharides drafted with polyesters (amphyphilic copolymers),poly(methylidene malonate), gelatin, poly(E-caprolactone), sodiumalginate, agarose hydrogel, PMMA, biotinylated poly(ethylene glycol)conjugated with lactobionic acid, poly(vinyl alcohol) hydrogel,biotinylated pullulan acetate, dib loc copolymers and mixtures thereof.Wherein the polycyanoacrylates are preferably, but not limited to:polybutylcyanoacrylate, polyhexylcyanoacrylate,polyethyl-cyano-acrylate, polyisobutylcyanoacrylate and mixtures thereof

The drug can be provided or released from the drug receiving layer andcoating of the present invention in a micro-encapsulated form.Micro-encapsulation of drugs is known in the art, such as“Microencapsulation Techniques, Factors Influencing EncapsulationEfficiency: A Review” Jyothi et. al Journal of Microencapsulation,Informa Health Care, Volume 27, Issue 3, P. 187-197, and is within theskill of the ordinary artisan.

The drug can be provided or released from the drug receiving layer andcoating of the present invention in a nanoencapsulated with anencapsulation material in nanoparticles. Nanoencapsulation of drugs isknown in the art, and is within the skill of the ordinary artisan.Non-limiting examples of nanoencapsulation materials include: chitosannanoparticles, human serum albumin nanoparticles; silica nanospheres,PEG'ylated core-shell nanoparticles, biodegradablePGGA(poly(D,L-lactide-co-glycolide) particles, PLA (poly lactic acid),PGA, PLG (poly-(D,L-glycolide) polymeric nanoparticles, biocompatiblegliadin nanoparticles, low pH sensitive PEG stabilized plasmid-lipidnanoparticles, tocopherol derivatives stabilized nano-sized emulsionparticles, PLA-PEG nanoparticles, nanoparticles composed of hydrophilicproteins coupled with apolipoprotein E, biodegradablepoly(vesiln-caprolactone) nanoparticles, biotinylated poly(ethyleneglycol) conjugated with lactobionic acid, carboxylmethyl dextranmagnetic nanoparticles and mixtures thereof.

The drug can be provided or released from the drug receiving layer andcoating of the present invention in an emulsion, water-in-oil emulsion,an oil-in-water emulsion, or a liposome. Emulsions, water-in-oilemulsions, oil-in-water emulsions and liposomes including drugs is knownin the art, such as U.S. Pat. No. 7,638,137 B2, and is within the skillof the ordinary artisan.

The drug of the present invention can take any appropriate form, such asa small molecule or a biologic or biologic mimic as those terms areknown in the art. As stated previously, a wide variety of drugs in manyforms are known for the treatment or prevention of a disease, disorderor condition. The present invention is not limited to any particulartype or classification of drug. The structures of the coating of thepresent invention can be tailored for the storage and release of anyappropriate drug. For example, the porosity of a drug reservoir layerwould tend to be greater for a larger molecule, and likewise less so fora small molecule. By way of example, a small molecule would includehormones for hormone replacement therapy or nucleoside analogues asanti-viral agents. Biological drugs and related biological mimics, byway of example, would include the general classifications of enzymes,transport proteins, structural proteins, storage proteins, hormoneproteins, receptor proteins, contractile proteins, defensive proteins,cytokines, clotting factors and vaccines. An example of a preferredproteins include, but are not limited to, insulin for the treatment ofdiabetes and antibodies and monoclonal antibodies for the treatment ofinfection or for targeted delivery of associated drugs.

In essence, virtually any drug can be useful in the present inventionand an enumerated listing is beyond the scope of this document. As wayof example, the following is a non-limited and non-exhaustive list ofgeneral classifications of drugs useful in the present invention: ananti-inflammatory, an anti-allergy, and antibiotic, a drug for thetreatment of glaucoma, a drug for the treatment of macular degeneration,an ophthalmic drug, a hydrophilic drug, a hydrophobic drug, ananti-parasitic drug, a steroid, an antibiotic and a medicament for thetreatment of dry eye and a medicament for treatment of eye discomfort.

Barrier Layer

The coating of the present invention can also include a barrier layer.In one aspect of the invention, the barrier layer is applied to the topof the drug reservoir layer and provides structure to the coating layerto modulate release of the drug from the coating and the coating. Thebarrier layer in this aspect of the invention can provide drug releasemodulating structures such as, but not limited to capillary structures.Multiple layers of barrier layers can be used as well to furthermodulate the release of drug from the drug reservoir layer and thecoating layer. In another aspect of the invention, a barrier layer canbe provided below the drug reservoir layer so as to prevent or diminishthe migration of a drug in one direction while allowing the drug tomigrate in another direction. Unlike the drug reservoir layer, thebarrier layer does not substantially sequester a drug or allow a drug topass through that structure, but rather modulates the flow of drug fromthe drug reservoir layer and the coating layer. The barrier layer can beprovided within the coating by any appropriate means, preferably but notlimited to printing technology.

The barrier layer can include a polymer with the characteristics statedabove. Preferable polymers include, but are not limited to silicone,polyhydroxyethylmethylacrylates (polyhema, PVA, poly-n-vinyl pyrolidone,and polycarbonates). Depending on the polymer and the printingtechnology chosen, the polymer can be provided in a monomer state andlater polymerized, or in the alternative, provided in a polymerizedstate.

The barrier layer can also include a partially polymerized polymer withthe characteristics stated above and can be any as appropriate.Preferable polymers include, but are not limited to silicone,polyhydroxy ethylmethylacrylates (polyhema, PVA, and polycarbonates).Depending on the partially polymerized polymer and the printingtechnology chosen, the partially polymerized polymer can be provided ina monomer state and later partially polymerized, or in the alternative,provided in a partially polymerized state.

The barrier layer can include a polymer matrix with the characteristicsstated above and can be any as appropriate. Preferable polymer matrixinclude, but are not limited to, proteins, nucleic acids, andcarbohydrates silicone, polyhema, and polycarbonates). Depending on thepolymer and the printing technology chosen, the polymer matrix can beprovided in a monomer state and later polymerized, or in thealternative, provided in a polymerized state.

In addition, still other materials can be used for the barrier, such as,but not limited to silicone, ceramic, glass, carbon (inclusive ofnanotubles and graphite) and fabric. The silicone, ceramic, glass,carbon and fabric can be any appropriate and as are realized in the artand the choice generally relates, as with other materials used in thebarrier layer, to they physical characteristics such as the ability togenerally accept and not retain a drug for later release and compatiblewith the printing technology chosen to print the barrier layer, can makepermanent bond or dissolve in solvent or washable with solvent rinse.

Preferable materials for the barrier layer include derivatizedoligomers. Preferable derivatized oligomers include, but are not limitedto HEMA, DMA, GMA, PVA, silicone or siloxane. As with other materialsused, the choice of derivatized oligomers depends on the physicalcharacteristics of the material and the printing technology used to makethe drug barrier layer.

If the material used for the barrier layer need to be polymerized andcured, then a polymerization initiator or curing initiator needs to beused. The requirement for a polymerization initiator or curing initiatordepends on the particular type of polymer/monomer being utilized and thechoice is established in the technology. Preferable polymerizationinitiator or curing initiators include, but are not limited to at leastone of UV cure, thermal cure, room temperature cure, simultaneousprinting and UV curing or e-beam.

In one preferred aspect of the present invention, the barrier layerincludes capillary structures in order to modulate the release or flowof drug from the drug reservoir layer and the coating layer in general.These capillary structures are of a shape, size, orientation and spacingin order to allow capillary action to modulate the flow of drug from thedrug reservoir layer and out of the coating layer.

The Lucas-Washburn equation that predicts the rise of the fluidmeniscus, H(t), in the capillary with time t is given as:H(t)=[(sR cos {acute over (Ø)}/2n)^(1/2) t ^(1/2)

Where:

-   -   s=fluid surface tension    -   n=fluid shear viscosity    -   R=pore radius    -   {acute over (Ø)}=contact angle between meniscus and wall        (Ref D. I. Dimitrov 1, A. Milchev 1,2, and K. Binder 1

-   1Institut für Physik, Johannes Gutenberg Universitát Mainz,    Staudinger Weg 7, 55099 Mainz, Germany

-   2Institute for Chemical Physics, Bulgarian Academy of Sciences, 113    Sofia, Bulgaria, Received 30 Mar. 2007; published 31 Jul. 2007)

One can use this equation to determine the drug release rateR_(capillary) for a capillary of given height, diameter, contact angle,viscosity and surface tension. The diameter and height of capillariesare at nano level, for example. they may be less than about 5 nanometersto about 50,000 nanometers.

Printing

A wide variety of printing technologies are applicable to providing thevarious layers of the coating of the present invention. The choice ofwhich printing technology to use is a matter of choice for the skilledartisan based on the particular size, shape, thickness and othercharacteristics of the layer being provided. In addition, as some of thelayers are printed in liquid or semi-solid form and then transformedinto a solid or semi-solid form by, for example but not limited topolymerization or partial polymerization, the characteristics of theprinting liquid or semi-solid is to be taken into account. As apreferred aspect of the present invention, the compositions of Doshi etal., published U.S. application No. 2008/0062381A1, published Mar. 13,2008, are applicable, particularly when the pigment is optionallypresent in such formulations, and at least one drug is optionallyprovided in such formulations.

Preferred printing methods are digital in nature, such as thosedescribed by Doshi et al. (U.S. 2008/0062381A1) which is incorporated byreference herein in its entirety, such that they allow for a relativelyprecise method and means to provide a high quality and well definedprint product. As the method and associated device are digital innature, the printing process is adaptable for computer control andproduct design. Preferred digital printing methods and structures arediscussed herein. As a non-limiting introduction to digital printingmethods and devices, the following digital printing methods arepreferred: ink jet printing, three dimensional printing (3D printing),piezo printing, thermal printing, laser printing MEMS printing(Micromachined Electro-Mechanical System) wherein the printing head orrelated or associated structures are rotatable or non-rotatable.Generally, but not exclusively, a printing solution of the presentinvention replaces the ink solution of existing and commerciallyavailable printing devices, in particular within the printing cartridge.

Likewise, preferred printing methods include pad printing as thosemethods are known in the art, including but not limited to pad transferprinting. Pad printing is not as exact as digital printing, but is apreferred method of printing for the present invention. Pad printing isknown in the art for printing of images of the iris of the eye oncontact lenses (see, for example, U.S. Pat. Nos. 5,302,978, 5,414,477,and 4,668,240).

Ink jet printing is known in the art and can take various forms andassociated structures as are discussed herein. Generally, ink jetprinting refers to printing devices and methods that utilize highlyprecise printing methods and structures that allow for the production ofhigh quality and precise structures. Generally, available ink jetprinting devices and structures can be utilized with minimalmodification, with the ink solutions normally present in the ink jetcartridge or reservoir is replaced with a solution that includes apolymerizable monomer and associated polymerization initiators asneeded. The polymerizable monomer can be polymerized at will and at arapid rate after being dispensed from the ink jet printing structure.

Three dimensional printing is based primarily, but not exclusively, onink jet printing technologies. These methods and devices allow for thegeneration of one-off or multiple copies of a structures. Generally, apolymerizable solutions is placed within the printing device and isdispensed under computer control and polymerized in repeated printingcycles or steps to generate a three dimensional structure. Examples ofavailable and preferred 3D printing devices and related structures andcartridges include, but are not limited to those disclosed herein andotherwise known in the art or later developed.

Piezo printing is a subtype of ink jet printing that is a preferableprinting method of the present invention. Examples of available andpreferred piezo printing devices and related structures and cartridgesinclude, but are not limited to those disclosed herein and otherwiseknown in the art or later developed.

Thermal printing is a subtype of ink jet printing that is a preferableprinting method of the present invention. Examples of thermal printingdevices and related structures and cartridges include, but are notlimited to those disclosed herein and otherwise known in the art orlater developed.

Laser printing is a subtype of ink jet printing that is a preferableprinting method of the present invention. Examples of laser printingdevices and related structures and cartridges include, but are notlimited to those disclosed herein and otherwise known in the art orlater developed.

Optionally, an ink jet printing device can include a rotating printerhead that can allow for enhanced printing on curved surfaces.

Another preferred printing method is MEMS printing, wherein MEMS standsfor Micromachined electromechanical system and is based on technologiesthat allow for the printing of integrated circuit boards, but areapplicable to the production of very small structures that havefunctionality. Examples of structures having functionality made by MEMSprinting include mechanical gears and other mechanical devices, lab on achip structures for the performance of laboratory procedures includingchemical reactions and diagnostic procedures

Modulation of Release of Drug

The combination of the components of the coating of the presentinvention, in particular the at least one drug reservoir layer thatincludes at least one drug and the at least one barrier layer,optionally with structures, such as but not limited to capillarystructures, allows for the controlled release of the at least one drugfrom the coating. The coating structure allows for the production of acoating layer that can particularly tailor the release of the at leastfrom drug from the coating layer for desirable characteristics, such as,but not limited to, dose, regime, time course of delivery and route ofadministration. As the article of manufacture can be localized to aparticular locus on a subject, the drug can be delivered with particularfocus with a particular regime, which can allow for less drug beingadministered to a subject if it were otherwise administered in a moresystematic route of administration. The particular physical chemistryphenomenon associated with the release of the drug from the coatinglayer are discussed herein, but the listing is not to be consideredlimiting.

In one aspect of the invention, the release of the at least one drugfrom the coating layer can be modulated by diffusion, first out of thedrug reservoir layer and then through the barrier layer, if present.Determination of the effect of diffusion on the migration of a chemicalentity through a substrate or structures that can be a part of thecoating layer can be made using established methods, formulas andthrough routine experimentation.

In another aspect of the invention, the release of the at least one drugfrom the coating layer can be modulated by diffusion, first out of thedrug reservoir layer and then through the barrier layer which caninclude structures, such as capillary structures (see, FIG. 4).Determination of the effect of capillary action on the migration of achemical entity through a capillary structure present in the coatinglayer of the present invention, in particular the barrier layer, can bemade using established methods, formulas and through routineexperimentation.

In another aspect of the invention, the release of the at least one drugfrom the coating layer can be modulated by mass action, first out of thedrug reservoir layer and then through the barrier layer which caninclude structures, such as capillary structures. Determination of theeffect of mass action on the migration of a chemical entity through acoating layer of the present invention, can be made using establishedmethods, formulas and through routine experimentation.

In yet another aspect of the invention, the release of the at least onedrug from the coating layer can be modulated by a concentration gradientof the at least one drug, first out of the drug reservoir layer and thenthrough the barrier layer which can include structures, such ascapillary structures. Determination of the effect of a chemical gradienton the migration of a chemical entity through a coating layer of thepresent invention, can be made using established methods, formulas andthrough routine experimentation.

In yet another aspect of the invention, the release of the at least onedrug from the coating layer can be modulated by the solubility of the atleast one drug in an environment, first out of the drug reservoir layerand then through the barrier layer which can include structures, such ascapillary structures. Determination of the effect of a solubility on themigration of a chemical entity through a coating layer of the presentinvention, can be made using established methods, formulas and throughroutine experimentation.

In yet another aspect of the invention, the release of the at least onedrug from the coating layer can be modulated by the temperature at whichthe article of manufacture is held (either at storage temperature orduring use) of the at least one drug, first out of the drug reservoirlayer and then through the barrier layer which can include structures,such as capillary structures. Determination of the effect of temperatureon the migration of a chemical entity through a coating layer of thepresent invention, can be made using established methods, formulas andthrough routine experimentation.

In yet another aspect of the invention, the release of the at least onedrug from the coating layer can be modulated by the molecular weight ofthe at least one drug, first out of the drug reservoir layer and thenthrough the barrier layer which can include structures, such ascapillary structures. Determination of the effect of molecular weight onthe migration of a chemical entity through a coating layer of thepresent invention, can be made using established methods, formulas andthrough routine experimentation.

In yet another aspect of the invention, the release of the at least onedrug from the coating layer can be modulated by a concentration gradientof the at least one drug, first out of the drug reservoir layer and thenthrough the barrier layer which can include structures, such ascapillary structures. Determination of the effect of the migration of achemical gradient on a chemical entity through a coating layer of thepresent invention, can be made using established methods, formulas andthrough routine experimentation.

In further aspect of the invention, the release of the at least one drugfrom the coating layer can be modulated by the thickness of the coatinglayer, and the components thereof, namely the drug reservoir layer andthe barrier layer, if present, and ancillary structures, such acapillary structures, if present. Determination of the effect of thethickness of the coating and the components thereof on the migration ofa chemical entity through a coating layer of the present invention, canbe made using established methods, formulas and through routineexperimentation.

In a still further aspect of the invention, the release of the at leastone drug from the coating layer can be modulated by the porosity of thecoating layer, and the components thereof, namely the drug reservoirlayer and the barrier layer, if present, and ancillary structures, sucha capillary structures, if present. Determination of the effect of theporosity of the coating and the components thereof on the migration of achemical entity through a coating layer of the present invention, can bemade using established methods, formulas and through routineexperimentation.

In a still further aspect of the invention, the release of the at leastone drug from the coating layer can be modulated by the pore size of thecoating layer, and the components thereof, namely the drug reservoirlayer and the barrier layer, if present, and ancillary structures, sucha capillary structures, if present. Determination of the effect of thepore size of the coating layer and the components thereof on themigration of a chemical entity through a coating layer of the presentinvention, can be made using established methods, formulas and throughroutine experimentation.

In a still further aspect of the invention, the release of the at leastone drug from the coating layer can be modulated by the molecularexclusion size of the coating layer, and the components thereof, namelythe drug reservoir layer and the barrier layer, if present, andancillary structures, such a capillary structures, if present.Determination of the effect of the molecular exclusion size of thecoating and the components thereof on the migration of a chemical entitythrough a coating layer of the present invention, can be made usingestablished methods, formulas and through routine experimentation.

In another aspect of the invention, the release of the at least one drugfrom the coating layer can be modulated by the water content of thecoating layer, and the components thereof, namely the drug reservoirlayer and the barrier layer, if present, and ancillary structures, sucha capillary structures, if present. Determination of the effect of thewater content of the coating and the components thereof on the migrationof a chemical entity through a coating layer of the present invention,can be made using established methods, formulas and through routineexperimentation.

In yet another aspect of the invention, the release of the at least onedrug from the coating layer can be modulated by the concentration of thedrug in the coating layer, and the components thereof, namely the drugreservoir layer and the barrier layer, if present, and ancillarystructures, such a capillary structures, if present. Determination ofthe effect of the concentration of the drug in the coating and thecomponents thereof on the migration of a chemical entity through acoating layer of the present invention, can be made using establishedmethods, formulas and through routine experimentation.

In a further aspect of the invention, the release of the at least onedrug from the coating layer can be modulated by the concentration of thedrug in the coating layer, and the components thereof, namely the drugreservoir layer and the barrier layer, if present, and ancillarystructures, such a capillary structures, if present. Determination ofthe effect of the concentration of the drug in the coating and thecomponents thereof on the migration of a chemical entity through acoating layer of the present invention, can be made using establishedmethods, formulas and through routine experimentation.

In a still further aspect of the invention, the release of the at leastone drug from the coating layer can be modulated by the packagingenvironment of the coating layer (such as the concentration of drug inthe packaging solution, if present), and the components thereof, namelythe drug reservoir layer and the barrier layer, if present, andancillary structures, such a capillary structures, if present.Determination of the effect of the packaging environment of the coatingand the components thereof on the migration of a chemical entity througha coating layer of the present invention, can be made using establishedmethods, formulas and through routine experimentation.

In one aspect of the invention, the drug can exhibit sustained releaseover time from the coating layer. This can be achieved by firstestablishing the relationship of release rate of a given drug for agiven material of barrier layer in terms of thickness variation, drugsolubility, concentration. In another aspect of the invention, the drugcan exhibit intermittent release over time from the coating layer.

In yet another aspect of the invention, more than one drug can bereleased from the coating layer of the present invention. This aspect ofthe invention is depicted in FIG. 8 wherein different areas of thecoating layer have different drugs provided in the drug reservoir layer.In the alternative, more than one drug can be provided in a single drugreservoir layer.

Contact Lens

In one preferred aspect of the present invention, the medical deviceincludes a contact lens. Contact lenses that include a drug, on thesurface of the contact lens or within the contact lens are known in theart. However, these contact lenses do not provide the structures of thepresent invention, such as the at least one coating that includes atleast one drug reservoir layer that can include at least one drug, andat least one barrier layer that can include structures, wherein therelease of the at least one drug from the at least one coating layer ismodulated by

A variety of materials are known in the art for making contact lensesand are useful in the present invention. Preferred materials include,but are not limited to, acrylics, silicones, polyvinylalcohols, andcombinations thereof.

There are a variety of general types of contact lenses known in the artand are useful in the present invention. Preferred general types ofcontact lenses include, but are not limited to hybrid lenses,hydrophilic lenses and hydrophilic lenses.

In addition, there are other general types of contact lenses known inthe art and are useful in the present invention. These lenses include,but are not limited to spherical lenses, toric lenses, multifocallenses, tinted lenses, corrective optical power lenses and lenseswithout corrective optical power.

There are a variety of methods used to make lenses that are useful inthe present invention. Preferred methods of making, at least in part orin combination, contact lenses include, but are not limited to, lathing,cast molding, spin casting and ink jet printing.

Once a contact lens is manufactures, a variety of secondary or finishingoperations can be utilized and are useful in the present invention.Preferred secondary or finishing operations include, but are not limitedto edging, polishing, tinting, hydration, extraction, and sterilization.

In one aspect of the present invention, the at least one drug in an atleast one coating layer can be provided on the surface of a contactlens. In another aspect of the present invention, the at least one drugin at least one coating layer can be provided within a contact lens. Inanother aspect of the present invention, the at least one drug can beprovided inside a contact lens without the structures in an at least onecoating layer in combination with at least one drug in at least onecoating layer on the surface of a lens. In yet another aspect of thepresent invention, the at least one coating layer with at least one drugcan be provided both on the surface of the lens and inside the lens.

In some cases, drugs provided within the at least one coating can haveoptical properties that can interfere with the optical function of thecontact lens, such as drugs having coloring or opaqueness. Preferreddrugs for use in the present invention do not have such opticalproperties, but that need not be the case as drugs having such opticalproperties are useful in the present invention.

In another aspect of the present invention, the one or more coatings canoptionally dispersed therein nanoparticles having a particles size lessthan about 50 nm, a nanoencapsulated ophthalmic drug from which theophthalmic drug is able to diffuse into and migration through thecontact lens and into the post-lens tear film or towards the eyelid whenthe contact lens is placed on the eye, the nanoparticles being dispersewithin the contact lens or on at least one surface of the contact lensin an amount such that the lens optionally remains substantiallyoptically transparent (see, for example, U.S. Pat. No. 7,638,137B2 toChauhan et al., issued Dec. 29, 2009).

In another aspect of the present invention, the one or more coatings canoptionally dispersed therein nanoparticles having a particles size lessthan about 50 nm, a nanoencapsulated ophthalmic drug from which theophthalmic drug is able to diffuse away from and migrate away from thecontact lens and into the post-lens tear film or towards the eyelid whenthe contact lens is placed on the eye, the nanoparticles being dispersewithin the contact lens or on at least one surface of the contact lensin an amount such that the lens optionally remains substantiallyoptically transparent (see, for example, U.S. Pat. No. 7,638,137B2 toChauhan et al., issued Dec. 29, 2009).

In yet another aspect of the present invention, when the at least onedrug is provided with or without a drug delivery compositions asdescribed herein, the at least one drug as provided with or without adrug delivery compositions is substantially optically transparent.However, this need not be the case. In one aspect of the presentinvention, when the at least one drug as provided with or without a drugdelivery composition is substantially optically transparent or is notsubstantially optically transparent, the optical characteristics of theat least one drug, or other structures of the at least one coatinglayer, can be masked with opaque material or tinting, such as colortinting as is known in the art.

Packaging

The article of manufacture of the present invention can be provided in avariety for forms and packaging formats and solutions as present. Manyof these packaging form and formats are established packaging formats,whereas others are unique to the present invention.

The article of manufacture of the present invention can be provided in apackaging in a dry state, preferably in a dehydrated state or alyophilized state using methods know in the art. The article ofmanufacture of the present invention can also be provided in a packagingin a wet state, that is to say provided in an appropriate solution and,as appropriate, in a hydrated state.

The format of the packaging can be any as is appropriate. For example,the article of manufacture can be provided in packaging that isappropriate and normal for the article of manufacture, such as vials,other containers such as boxes or plastic containers, or in vials. Vialsand blister packaging are preferable, but not necessary, for example,for contact lenses.

The solution present, if any, in a packaging format, in particular for awet state packaging format can include the at least one drug present inthe at least one coating layer, a different drug that that provided inthe coating layer, or a combination thereof.

In one instance, the concentration of the drug in a packaging solutionis less than the concentration of the drug in the coating layer. In thatcase, it is likely that the drug in the coating layer may migrate fromthe coating layer into the packaging layer and eventually reach a steadystate equilibrium state, but that not be the case.

In another instance, the concentration of the drug in a packagingsolution is equal to the concentration of the drug in the coating layer.In that case, it is likely that the drug in the packaging solution willbe in steady state with the drug in the coating layer, but that need notbe the case.

In the alternative, the concentration of the drug in the packagingsolution is greater than the concentration of the drug in the coatinglayer. In that case, it is likely that the drug in the packagingsolution would migrate into the coating layer and eventually reach asteady state equilibrium state, but that need not be the case.

In yet another instance, a drug provided in the packaging layer that isnot present in the coating layer may be present. In that case, it islikely that the drug in the packaging solution would migrate into thecontact lens and eventually reach a steady state equilibrium state, butthat need not be the case.

II Methods of Making Medical Devices Including a Medicament

The present invention also includes a method of making an article ofmanufacture, comprising: a) providing a medical device including atleast one surface; b) depositing one or more coatings on at least aportion of the at least one surface, wherein the one or more coatingsincludes; 1) at least one drug reservoir layer deposited at least inpart by printing on the at least one surface, wherein the at least onedrug reservoir layer comprises at least one drug; and 2) at least onebarrier layer deposited at least in part by printing on at least aportion the at least one drug reservoir layer, wherein the at least onebarrier layer includes one or more structures. Particular examples ofthis aspect of the invention are presented diagrammatically in FIG. 1(see in particular steps 1 to 4).

The present invention also includes a method of making an article ofmanufacture, including: a) providing a medical device including at leastone surface; b) depositing one or more coatings on at least a portion ofthe at least one surface, wherein the one or more coatings comprises; 1)at least one barrier or blocking layer deposited at least in part byprinting on said at least one surface; and 2) at least one drugreservoir layer deposited at least in part by printing on said at leastbarrier layer, wherein said at least one drug reservoir layer comprisesat least one drug. Particular examples of this aspect of the inventionare presented diagrammatically in FIG. 7 steps A through C. Also asshown in FIG. 9, a blocking layer can be deposited inside a partiallypolymerized contact lens to achieve a unidirectional drug release.

Having discussed the particular structures of the present invention,what they are made of, how they are preferably made, how they interact,how they are assembled and how they are chosen based on their physicaland chemical nature, and the like, the discussion now turns to how thearticle of manufacture is made, with exemplary and preferred exampleslater provided in the examples section.

Medical Device

First, a medical device is chosen on which a coating is to be provided.Essentially any medical device can be used in the present invention. Thechoice of the medical device is one within the skill of the ordinaryartisan and the state of the art provides vast literature on a widevariety of medical devices and where they are to be implanted and whichdrugs would be useful to be provided with a coating of the presentinvention to treat or prevent any number of diseases, conditions ordisorders that a subject may suffer from.

The medical device can be implantable or non-implantable as those termsare known in the art and have been previously discussed. In onepreferred aspect of the present invention, the medical device includes acardiac stent or joint replacement apparatus, or other implantablemedical device. In another preferred aspect of the present invention,the medical device includes a contact lens or skin patch drug deliverymedical device, or other non-implantable medical device.

Surface

The medical device presents a surface upon which a coating of thepresent invention is to be made. The surface of the medical devicechosen is usually an inherent property of the medical device, but thatneed not be the case. The surface can be modified by any number ofmethods or techniques and known in the art and discussed herein,including chemical modification or physical modification.

In certain preferred aspects of the present invention, as discussedherein, the surface presented for the application of a coating of thepresent invention includes, but is not limited to, at least one metal,at least one plastic, at least one polymer, at least one partiallypolymerized polymer, at least one polymer matrix, at least one proteinmatrix, at least one silicone, at least one ceramic, at least one glass,at least one carbon containing compound, at least one fabric, or acombination thereof.

In other preferred aspects of the present invention, as discussedherein, the surface presented for the application of a coating of thepresent invention can be modified by a variety of methods before acoating of the present invention is applied thereto. Preferred surfacemodification methods include but are not limited to one or more chemicalprocesses or one or more physical processes. Preferred chemicalprocesses include, but are not limited to, chemical coating, chemicalcleaning, chemical texture modification, chemical or electrochemicalactivation or creation of reactive groups on or within said at least onesurface, application of one or more chemicals to said at least onesurface, and combinations thereof. Preferred physical processes includebut are not limited to, etching, scoring, spraying of materials on thesurface, sputtering of materials on the surface, corona treatment, andcombinations thereof.

Drug Reservoir Layer

The coating of the present invention includes a drug reservoir layer,which includes at least one drug for later release into or onto asubject at the locus where the medical device is provided to a subject.The drug reservoir layer is preferably provided directly on at least aportion of the surface of a medical device as discussed herein and isthe first component of the coating of the present invention. However, atleast one barrier layer may be provided before an at least one drugreservoir layer in certain aspects of the invention where the directionof release of a drug from a coating of the present invention is desired,(see, FIG. 7) such as the case where a medical device presents multiplesurfaces for release of a drug from a coating of the present invention,such as, for example, contact lenses where the drug can be releasedtowards the eye, towards the eyelid, or both.

The drug reservoir layer can be made of any appropriate material orcombination of materials, and the choice of material is generally withinthe skill of the art as influenced by a variety of factors, includingbut not limited to the printing method to be used to provide the drugreservoir layer, the size, thickness an shape of the drug receivinglayer desired, the physical and chemical properties desired for the drugreservoir as influenced by the chemical and physical characteristics ofthe drug provided in the drug receiving layer such that the drug can bereleased at a desired rate, and the like.

Preferred materials for the drug receiving layer include, but are notlimited to, at least one polymer, at least one partially polymerizedpolymer, at least one polymer matrix, at least one protein matrix, atleast one silicone, at least one ceramic, at least one glass, at leastone carbon containing compound, at least one fabric or a combinationthereof. Other preferred materials include, but are not limited to,derivatized oligomers, such as but not limited to, HEMA, DMA, GMA, PVA,silicone and siloxane, or combinations thereof.

In certain aspects of the present invention, during the printing processused to make the drug reservoir layer, a non-polymerized or partiallypolymerized printing formulation, which can include at least one drug,is applied to the surface. In that instance, the non-polymerized orpartially polymerized formulation is to be polymerized or otherwisecured to stabilize the drug receiving layer and, in certain aspects ofthe invention, serves to entrap or otherwise localize a drug in the drugreservoir layer for later release therefrom (see, FIG. 3). Preferredmethods for polymerizing or curing a drug reservoir when needed ordesirable include, but not limited to, at least one UV curing orpolymerization, at least one thermal curing or polymerization, at leastone room temperature curing or polymerization, at least one simultaneousprinting and curing or polymerization, at least one e-beam curing orpolymerization, or combinations thereof.

In certain aspects of the present invention, the drug reservoir layer isbonded to, permanently bonded to, or is not bonded to the surface. Inthis instance, reactive groups on the surface or the drug receivinglayer may chemically or physically interact to form chemical bonds, suchas covalent bonds, or physical bonds, such as short range interactions,such as but not limited to hydrogen bonds, van der Walls interactions,hydrophobic interactions, hydrophilic interactions, ionic interactionsand the like. The formation of these chemical or physical interactionsis dependent upon the chemical nature of the surface and the drugreservoir layer and can be determined by the artisan based on based onthe state of the art.

In another aspect of the present invention, as discussed herein, thedrug receiving layer can release a drug in one or more directions. Incertain cases, the drug receiving layer, based on the nature of themedical device and surface, can release a drug only in one direction asthe surface will prevent, or block, the release of drug in one directionas the drug is not able to substantially migrate into the surface ormedical devices based on the material presented. As discussed herein, ablocking layer may be provided to prevent a drug from migrating in onedirection. As discussed herein, a drug may be released in more that onedirection, such as the case of contact lenses. Certain preferredconfigurations of this aspect of the invention are exemplified in FIG.7.

Drug Receiving Layer

In one aspect of the present invention, the at least one drug reservoirincludes an at least one drug receiving layer. In this aspect of thepresent invention, the drug receiving layer is printed on the surface,as the drug reservoir layer with at least one drug is as describedherein, and an at least one drug is provided to said at least one drugreceiving layer to form a drug reservoir layer. The drug is provided tothe drug receiving layer my any appropriate method, such as by printingas described herein, but other methods of proving a drug to a drugreceiving layer can be used, such as, but not limited to, soaking,dipping and spin coating. As with other layers of the coating of thepresent invention, the drug receiving layer can be made of anyappropriate material or combination of materials, and the choice ofmaterial is generally within the skill of the art as influenced by avariety of factors, including but not limited to the printing method tobe used to provide the drug receiving layer, the size, thickness anshape of the drug receiving layer desired, the physical and chemicalproperties desired for the drug reservoir as influenced by the chemicaland physical characteristics of the drug provided in the drug receivinglayer such that the drug can be released at a desired rate, and thelike.

In one aspect of the present invention, the at least one drug reservoirlayer includes a chemical coating applied to the surface. In thealternative, the at least one drug receiving layer is applied to anotherlayer that has been previously applied to the surface, such as, but notlimited to, a barrier layer to produce a coating layer that released adrug in a particular directions from the coating as described herein.

In another aspect of the present invention, the printing formulationused to print the drug receiving layer can include materials, such aschemicals, to allow for the polymerization or curing of the printed drugreservoir layer, and in certain instances, to allow for the tailoring ofthe physical characteristics of the drug receiving layer that affect therelease of the drug therefrom as described herein, such as, but notlimited to porosity, diffusion rate of a drug, and the like. Thematerials used to obtain these objectives include, but are not limitedto bonding agents, cross linking agents, or a combination thereof. Theuse of bonding agents, cross linking agents, or combinations thereof toprovide materials with desirable physical characteristics for thepresent invention are known in the art and are replete in the literatureand adaptation to the present invention can be made usingexperimentation or mathematical modeling.

In one preferred aspect of the present invention, the drug receivinglayer includes a highly absorbent polymer. Preferred highly absorbentpolymers include, but are not limited to, at least onepolyvinylpyrrolidine homopolymer, at least one polyvinylpyrrolidonecopolymer, at least one polyacrylamide homopolymer, at least onepolyacrylamide copolymer, at least one polyacrylate homopolymer, atleast one polyacrylate copolymer, at least one proteinaceous material,at least one carbohydrate, or a combination thereof.

The drug reservoir can be applied to a surface or desired location usingany appropriate method or means as described herein or as known in theart. Preferred methods or means include but are not limited to, directcoating, application of droplets or microdroplets, ink jet printing,soaking, impregnation, spin coating, drip coating, screen coating, silkscreen coating, pad printing, or a combination thereof.

Drug

As discussed previously, the at least one drug reservoir layer of the atleast one coating of the present invention includes at least one drugprovided therein such that the at least one drug can be released fromthe at least one coating. In general, the choice of drugs to be providedin the coating layer are a matter of choice for the artisan, and thereis a vast body of literature, both patent and not patent, available tothe artisan to identify drugs that are effective to treat or prevent andisease, disorder or condition.

The drug can be provided in the coating in an amount sufficient suchthat when the drug is released from the coating it is provided in atherapeutically effective amount for the route of administration andlocation of the medical device of the present invention within or on thesubject. The physical characteristics of the coating of the presentinvention as discussed herein, such as, but not limited to, pore sizeand water content, can be taken into account when considering whatconcentration of drug to be provided in the coating of the presentinvention such that the appropriate amount of drug is released from thecoating of the present invention.

As discussed herein, a medical device of the present invention isprovided within or on a subject such that the drug is released at aparticular locus rather than systemically as with other drug deliverymethods, such as through injection or oral administration. This allowsfor the drug to be delivered at a particular location and preferably ata lower or more precise dose than would otherwise be obtainable. Thefocused delivery of a drug by the medical device of the presentinvention also would reduce the instance of side effects of drugs thatmore systemic routs of administration would be characterized because thetotal body load of a drug in a subject would be greatly reduced comparedto more systemic administration of a drug.

As discussed herein, the location of the drug delivery device isdeterminable by the nature of the medical device and the disease,disorder or condition to be prevented or treated. For example,implantable cardiac stents would be provided in blood vessels as is thenormal course of treatment, and contact lenses would normally beprovided on the eye, but this need not be the case.

The drug can be provided with the coating layer of the presentinvention, or released from the coating layer of the present inventionin a variety of forms. In one aspect of the present invention, the drugis provided in the coating layer or released from the coating layer atleast in part as a sole active ingredient without any other ingredientassociation that can alter the activity or deliverability of said atleast one drug. That is to say, the drug is provided or released in afree state and not associated with other chemical entities, such as drugdelivery chemical entities as described herein or known in the art.

In the alternative, the drug is provided in the coating layer orreleased from the coating layer at least in part in at least oneencapsulated form, at least one micro-encapsulated form, at least onenano-encapsulated form, in at least one emulsion, in at least onewater-in-oil emulsion, in at least one oil-in-water emulsion, or in atleast one liposome, or a combination thereof, as described herein or asknown in the art.

As described herein the drug provided in the coating layer or releasedtherefrom can be virtually any drug, including but not limited to smallmolecule drugs or biological drugs as they are known in the art. Thereis a vast body of literature, both patent literature and non-patentliterature for these types of drugs. A comprehensive list is beyond thescope of this document. Preferred classes of drugs are provided herein,and include, but are not limited to, at least one anti-inflammatorydrug, at least one anti-allergy drug, at least one antibiotic drug, atleast one drug for the treatment of glaucoma, at least one drug for thetreatment of macular degeneration, at least one ophthalmic drug, atleast one hydrophilic drug, at least one hydrophobic drug, at least oneanti-parasitic drug, at least one steroid drug, at least one medicamentfor the treatment of dry eye and at least one medicament for treatmentof eye discomfort, or a combination thereof.

In one preferred aspect of the present invention, the drug is providedin a coating layer or released from the coating layer in an at least oneencapsulated form. Preferred encapsulation materials are discussedherein and are known in the art, and include, but are not limited to atleast one biodegradable polycyanoacrylate, at least one biodegradablepoly(alkylcyanoacrylates), at least one biodegradable calcium phosphate,at least one legumin, at least one polysaccharides drafted withpolyesters (amphyphilic copolymers), at least one poly(methylidenemalonate), at least one gelatin, at least one poly(E-caprolactone), atleast one sodium alginate, at least one agarose hydrogel, at least onePMMA, at least one biotinylated poly(ethylene glycol) conjugated withlactobionic acid, at least one poly(vinyl alcohol) hydrogel, at leastone biotinylated pullulan acetate, at least one dibloc copolymers andcombinations thereof.

In another preferred aspect of the present invention, thepolycyanoacrulate are those disclosed herein or known in the art,including but not limited to, at least one polybutylcyanoacrylate, atleast one polyhexylcyanoacrylate, at least one polyethyl-cyano-acrylate,at least one polyisobutylcyanoacrylate and combinations thereof.

In one preferred aspect of the present invention, the drug is providedin a coating layer or released from the coating layer in ananoencapsulated form with a least one encapsulation material innanoparticles, a least one oil-in-water emulsion, at least onewater-in-oil emulsion or at least one liposome material, or acombination thereof. The nanoparticles, when present, can be anydisclosed herein or described in the art, including but not limited to,chitosan nanoparticle, human serum albumin nanoparticle; silicananospheres, PEG'ylated core-shell nanoparticles, biodegradablePGGA(poly(D,L-lactide-co-glycolide) particles, PLA (poly lactic acid),PGA, PLG (poly-(D,L-glycolide) polymeric nanoparticles, biocompatiblegliadin nanoparticles, low pH sensitive PEG stabilized plasmid-lipidnanoparticles, tocopherol derivatives stabilized nano-sized emulsionparticles, PLA-PEG nanoparticles, nanoparticles composed of hydrophilicproteins coupled with apolipoprotein E, biodegradablepoly(vesiln-caprolactone) nanoparticles, biotinylated poly(ethyleneglycol) conjugated with lactobionic acid, carboxylmethyl dextranmagnetic nanoparticles and combinations thereof.

Barrier Layer

The coating of the present invention includes at least one barrier. Thebarrier layer is preferably provided directly on at least a portion ofthe at least one drug reservoir layer the second component of thecoating of the present invention. However, at least one barrier layermay be provided before an at least one drug reservoir layer in certainaspects of the invention where the direction of release of a drug from acoating of the present invention is desired, such as the case where amedical device presents multiple surfaces for release of a drug from acoating of the present invention, such as, for example, contact lenseswhere the drug can be released towards the eye, towards the eyelid, orboth.

The drug barrier layer can be made of any appropriate material orcombination of materials, and the choice of material is generally withinthe skill of the art as influenced by a variety of factors, includingbut not limited to the printing method to be used to provide the drugreservoir layer, the size, thickness an shape of the drug receivinglayer desired, the physical and chemical properties desired for the drugreservoir as influenced by the chemical and physical characteristics ofthe drug provided in the drug receiving layer such that the drug can bereleased at a desired rate, and the like.

Preferred materials for the barrier layer include, but are not limitedto, at least one polymer, at least one partially polymerized polymer, atleast one polymer matrix, at least one protein matrix, at least onesilicone, at least one ceramic, at least one glass, at least one carboncontaining compound, at least one fabric or a combination thereof. Otherpreferred materials include, but are not limited to, derivatizedoligomers, such as but not limited to, HEMA, DMA, GMA, PVA, silicone andsiloxane, or combinations thereof

In certain aspects of the present invention, during the printing processused to make the barrier, a non-polymerized or partially polymerizedprinting formulation, is applied to the surface. In that instance, thenon-polymerized or partially polymerized formulation is to bepolymerized or otherwise cured to stabilize the barrier layer and, incertain aspects of the invention. Preferred methods for polymerizing orcuring a drug reservoir when needed or desirable include, but notlimited to, at least one UV curing or polymerization, at least onethermal curing or polymerization, at least one room temperature curingor polymerization, at least one simultaneous printing and curing orpolymerization, at least one e-beam curing or polymerization, orcombinations thereof.

In one preferred aspect of the present invention, the barrier layerincludes structures, particularly structures that can modulate therelease of a drug from the drug reservoir layer and the coating layer.The figures provide examples of such structures, and preferredstructures include, but are not limited to capillary structures. Thesestructures can be readily made using the printing methods of the presentinvention, and the size, shape and spacing can be chosen based on avariety of factors discussed herein, including but not limited to thechemical and physical characteristics of the drug passing through thebarrier layer upon being released from the drug reservoir layer, thematerial that the barrier layer is made of, and the resolution of theprinting technique used to make the barrier layer.

As discussed herein, the at least one drug does not substantially passthrough the barrier layer, but rather the barrier layer serves tomodulate the release of the drug from the coating of the presentinvention.

Printing

One aspect of the present invention is that the various components ofthe at least one coating are preferable made using at least one printingtechnology. The components of the coating include, but are not limited avariety of layers, including but not limited to, and may not include allof the listed components, at least one drug reservoir layer, at leastone drug receiving layer, and at least one barrier layer. The same ordifferent printing technologies can be used to make the variouscomponents. Likewise, one or more printing technologies can be used tomake a particular component. The printing of the various components, orlayers, preferably uses a printing formulation of the present invention,but that need not be the case. Printing formations of the presentinvention are described in further detail herein.

A wide variety of printing technologies are applicable to providing thevarious layers of the coating of the present invention. The choice ofwhich printing technology to use is a matter of choice for the skilledartisan based on the particular size, shape, thickness, printingresolution and other characteristics of the layer being provided. Oneskilled in the art would have available technical literature to matchthe desired characteristics of the layer to be printed with thecharacteristics, benefits and limitations of a printing technology.Likewise, one skilled in the art would be able to match a printingformation used to make a layer of the present invention with aparticular printing technology, and the desired characteristics of thelayer to be printed as well.

The characteristics of the printing formulation being used to make thelayer, such as, but not limited to the viscosity and surface tension ofthe printing formation. Also, the nature of the printing device incombination with the printing formation is a factor to consider, such asthe case when a printing technology, such as but not limited to ink jetprinting technology utilize printing structures that may requirerelatively stringent physical and chemical characteristics of theprinting solution such that the printing formulation does not clog orotherwise damage or interfere with the printing device.

In addition, as some of the layers are printed in liquid or semi-solidform and then transformed into a solid or semi-solid form by, forexample but not limited to polymerization or partial polymerization, thecharacteristics of the printing liquid or semi-solid is to be taken intoaccount. As a preferred aspect of the present invention, thecompositions of Doshi et al., published U.S. application No.2008/0062381A1, published Mar. 13, 2008, are applicable, particularlywhen the pigment is optionally present in such formulations, and atleast one drug is optionally provided in such formulations.

Preferred printing methods are digital in nature, such as thosedescribed by Doshi et al. (U.S. 2008/0062381A1) which is incorporated byreference herein in its entirety, such that they allow for a relativelyhighly precise method and means to provide a high quality and welldefined print product. As the method and associated device are digitalin nature, the printing process is adaptable for computer control andproduct design. Preferred digital printing methods and structures arediscussed herein. As a non-limiting introduction to digital printingmethods and devices, the following digital printing methods arepreferred: ink jet printing, three dimensional printing (3D printing),piezo printing, thermal printing, laser printing MEMS printing, whereinthe printing head or related or associated structures are rotatable ornon-rotatable. Generally, but not exclusively, a printing solution ofthe present invention replaces the ink solution of existing andcommercially available printing devices, in particular within theprinting cartridge.

Likewise, preferred printing methods include pad printing as thosemethods are known in the art, including but not limited to pad transferprinting. Pad printing is not as exact as digital printing, but is apreferred method of printing for the present invention. Pad printing isknown in the art for printing of images of the iris of the eye oncontact lenses (see, U.S. Pat. Nos. 5,414,477, 5,302,978, and4,668,240).

Ink jet printing is known in the art and can take various forms andassociated structures as are discussed herein. Generally, ink jetprinting refers to printing devices and methods that utilize highlyprecise printing methods and structures that allow for the production ofhigh quality and precise structures. Generally, available ink jetprinting devices and structures can be utilized with minimalmodification, with the ink solutions normally present in the ink jetcartridge or reservoir is replaced with a solution that includes apolymerizable monomer and associated polymerization initiators asneeded. The polymerizable monomer can be polymerized at will and at arapid rate after being dispensed from the ink jet printing structure.

Three dimensional printing is based primarily, but not exclusively, onink jet printing technologies. These methods and devices allow for thegeneration of one-off or multiple copies of a structure or structures.Generally, a polymerizable solutions is placed within the printingdevice and is dispensed under computer control and polymerized inrepeated printing cycles or steps to generate a three dimensionalstructure. Examples of available and preferred 3D printing devices andrelated structures and cartridges include, but are not limited to: 3DSystems (www.3dsystems.com/default.asp) (Mar. 29, 2011), ProJet™ 6000Professional 3D Printer(http://printin3d.com/sites/printin3d.com/files/downloads/Projet_6000_brochure_USEN.pdf)(Mar. 29, 2011); Stratasys, Inc. (http://www.stratasys.com/); Fortus 3DProduction Systems—Fortus 900mc; Z Corporation (www.zcorp.com);Zprinter® 650(http://www.zcorp.com/en/Products/3D-Printers/ZPrinter-650/spage.aspx)Vertical Resolution—90 to 100 microns (0.0035 to 0.004 in) SmallestFeature—100 microns (0.004 in); 3D Systems(http://www.3dsystems.com/default.asp); and Viper si2™ SLA® Systemhttp://www.3dsystems.com/products/datafiles/viper/datasheets/Viper_final_rev_0303.pdf.

Piezo printing is a subtype of ink jet printing that is a preferableprinting method of the present invention. Examples of available andpreferred piezo printing devices and related structures and cartridgesinclude, but are not limited to: MicroFab Technologies, Inc.(www.microfab.com) (Mar. 29, 2011); Jetlab® 4xl, 4xl-A((http://www.microfab.com/equipment/pdf/jetlab4xl_xla.pdf) (Mar. 29,2011); X-Y Accuracy/Repeatability—+/−25 microns/+/−5 microns (4xl-A);O.N.E Technologies (www.onelabs.com) (Mar. 29, 2011); MaterialDeposition Systems (www.onelabs.com/matdep00.htm) (Mar. 29, 2011),Resolution as low as 0.2 nanometer; Multi-Axis Printing Systems(www.onelabs.com/maxp00.htm) (Mar. 29, 2011); FujiFilm USA|Dimatix, Inc.(http://www.dimatix.com/index.asp) (Mar. 29, 2011); Dimatix MaterialsPrinter DMP-5000 (http://www.dimatix.com/files/DMP-5000-Datasheet.pdf)(Mar. 29, 2011) X-Y Accuracy/Repeatability—+/−5 microns/+/−1 microns;Mimaki JF Series (http://www.mimakiusa.com) (Apr. 1, 2011) Model JF1610or JF 1631(http://www.mimakiusa.com/IndustrialProduct.aspx?level=3&pid=3&cid=14)(Apr. 1, 2011), resolution up to 1200 by 1200 dpi.

Thermal printing is a subtype of ink jet printing that is a preferableprinting method of the present invention. Examples of thermal printingdevices and related structures and cartridges include, but are notlimited to: Hewlett Packard (www.hp.com) (Apr. 1, 2011); HP DesignjetH45000 Printer Serieshttp://www.hp.com/united-states/colorspan/djh45000-datasheet.pdf (Apr.1, 2011).

Laser printing is a subtype of ink jet printing that is a preferableprinting method of the present invention. Examples of laser printingdevices and related structures and cartridges include, but are notlimited to those known in the art such as Xerox Phaser 6010 laserprinterhttp://www.xerox.ca/office/printers/colour-printers/phaser-6010/spec-enca.htmlor HP Color LaserJet Enterprise CP4025 Printer series—HP Color LaserJetEnterprise CP4025dn Printer (CC490A)http://h10010.www1.hp.com/wwpc/us/en/sm/WF06b/18972-18972-3328060-15077-236268-3965792-3965795-3974244.html,or those later developed.

Optionally, a printing device, such as but not limited to an ink jetprinting device, can include a rotating printer head. These types ofprinting structure can allow for enhanced printing on curved surfaces.

Another preferred printing method is MEMS printing is based ontechnologies that allow for the printing of integrated circuit boards,but are applicable to the production of very small structures that havefunctionality. Examples of structures having functionality made by MEMSprinting include mechanical gears and other mechanical devices, lab on achip structures for the performance of laboratory procedures includingchemical reactions and diagnostic procedures.

Another preferred printing method is MEMS printing and is based ontechnologies that allow for the printing of integrated circuit boards,but are applicable to the production of very small structures that havefunctionality. Examples of structures having functionality made by MEMSprinting include mechanical gears and other mechanical devices, lab on achip structures for the performance of laboratory procedures includingchemical reactions and diagnostic procedures.

Printable Formulation

Printable formulations useful in the present invention for printing oflayers or structures of the present invention using printingtechnologies as discussed herein and known in the art, particularlydigital printing methods and technologies, can optionally include one ormore drugs, any single drug compound or composition, or any combinationof drug compounds or compositions. Printable formulations can beprovided in water, monomer or solvents, preferably at a concentrationbetween about 0% and greater than about 99.5% or between about 0.001%and about 99.5%, preferably between about 0.005% and about 90% orbetween about 1% and about 80%, and more preferably between about 10%and about 60% or between about 20% and about 40%. Printable formulationscan also include particles or particulates, preferably at aconcentration of between about 0% and about 15% or between about 0.001%and about 10%, preferably between about 0.005% and about 4% or betweenabout 1% and about 3% to render a digitally printed formulationoptionally with at least one drug. Examples of drugs include, but arenot limited to, Timolol, Gentamycin and Nevanac. As discussed herein,the characteristics and compositions including printable formulationsand other components include printable formulations that are or becomepart of an article of manufacture of the present invention, such as alens, such as a contact lens, and also include compositions that includeat least one printable formulations that can be used to make any articleof manufacture of the present invention.

Printable formulations can include water, monomer, polymer or anappropriate solvent in order for the printable formulations to besuitable in the making of a digital print. An appropriate solvent is asolvent that is compatible with the creation of a print such as adigital print on or within a surface, such as on or within a polymer.For example, solvents appropriate for polymers used to make lenses, suchas contact lenses, include, but are not limited to isopropanol, water,acetone or methanol, either alone or in combination and can include amonomer. Appropriate concentrations of solvents are between about 0% andgreater than about 99.5% or between about 0.1% and about 99.5%,preferably between about 1% and about 90% or between about 10% and about80%, and more preferably between about 20% and about 70% or betweenabout 30% and about 60%. Different polymers, monomers and printableformulations have different tolerances and reactivity to differentsolvents. Thus, appropriate matches between solvent and polymer, monomerand printable formulations can be considered. For hydrogel polymers,adjustment in swelling ratios may be achieved with a variety ofconcentrations of solvents or crosslinkers.

A printable formulation can also include a monomer, polymer,homopolymer, heteropolymer, or copolymer. In a preferred aspect of thisaspect of the present invention, a printable formulation includes amonomer that can be polymerized to form a polymer using polymerizationmethods appropriate for a given monomer, mixtures thereof, or polymers,or mixtures thereof. Monomers can also be used to decrease the viscosityof the printable formulation. Alternatively, the printable formulationcan include a polymer such that the viscosity of the printableformulation is increased. Alternatively, the printable formulation caninclude polymer and monomer. Appropriate concentrations of monomers arebetween about 5% and greater than 99%, preferably between about 25% andabout 75%, and more preferably between about 35% and about 60%.Appropriate concentrations of polymers are between about 0% and about50%, preferably between about 5% and about 25%, and more preferablybetween about 10% and about 20%. When monomers and polymers are mixed,the total concentration of monomer and polymer are between about 10% andgreater than 99%, preferably between about 25% and about 75% and morepreferably between about 35% and about 65%.

The viscosity of a solution including a printable formulation can be ashigh as between about 500 centipoise and about 5,000 centipoise and ispreferably between about 1 to about 200 centipoise or between about 10and about 80 centipoise, preferably between about 20 and about 70centipoise or between about 30 and about 60 centipoise or between about1 and about 10 centipoise. Solutions having low viscosity tend to be“runny” when dispensed, and can allow different colors to merge andblend, resulting in an image with a more natural appearance. Suchblending can be enhanced using a variety of methods, includingsonication or vibration at appropriate duration and frequency to promoteappropriate blending. Solutions having too low a viscosity can result inimages that are too “runny” and thus have potentially undesirablecharacteristics, such as pooling of a printable formulation in adigitally encoded image or spreading of a printable formulation to anunintended location. Solutions having too high a viscosity may be easilydispensed using pad printing but are not suitable for other printing.Furthermore, solutions having high viscosity can tend to “bead” on asurface and not blend with the surrounding environment, includingsurrounding droplets or beads of printing formulation. Agents such asthickeners or diluents (including appropriate solvents) can be used toadjust the viscosity of the printable formulation.

Alternatively, one may use drug receiving layer that holds inkjetteddigital droplets in its place until fixed. Another approach can be touse printable formulations that uses derivatized oligomer to be able tostop it from running by instant curing. Both of these approaches arediscussed herein.

A printable formulation that includes at least one monomer can alsoinclude a polymerization initiator, so that once a printable formulationthat includes at least one type of monomer is dispensed, thepolymerization of the monomer in the printable formulation is initiated.The number, type and amount of initiator is a matter of choice dependingon the type of monomer or monomers in the printable formulation.Appropriate initiators include, but are not limited to, UV initiatorsthat initiate polymerization by UV irradiation, thermal initiators thatinitiate polymerization by thermal energy.

A printable formulation can also include a dispersant to allow uniformcomposition of formulation in a container. Dispersants are preferablyprovided at an appropriate concentration, such as between about 1% andabout 10%.

A printable formulation can also include at least one anti-microbialagent or antiseptic agent to kill or reduce the number or multiplicationmicrobial agents, reduce the number of microbial agents, or keepmicrobial agents from multiplying. Preferred anti-microbial agentsinclude anti-bacterial agents, anti-fungal agents and disinfectants.Preferably, such anti-microbial agents, anti-bacterial agents,anti-fungal agents and disinfectants are provided at an appropriateconcentration such as between about 0% and about 1%.

A printable formulation can also include at least one humectant such as1,3-diozane-5,5-dimethanol (U.S. Pat. No. 5,389,132) at an appropriateconcentration. Preferably, the range of concentration of a humectant isbetween about 0% and about 2%.

A printable formulation can also include at least one antioxidant agentor a low corrosion agent, such as alkylated hydroquinone, at anappropriate concentration, such as between about 0.1% and about 1% (U.S.Pat. No. 4,793,264). A PF can also include a non-kogating agent ornon-kogating agent, such as 2-methyl-1,3-propanediol at an appropriateconcentration, such as between about 0% and about 1%. A printableformulation can also include an evaporation retarding agent, such as,for example, diethylene glycerol or ethylene glycol at between about 0%and about 2% (U.S. Pat. No. 5,389,132).

A preferred printable formulation can have the following composition:

Component Percentage Monomer 0% to 99% Drug or Encapsulated Drug 0% to25% Initiator 0.01% to 2% Solvent 0% to 80% Binder or Bonding Agent 0%to 10% Thickener 0% to 1% Anti-kogating Agent 0% to 1% Humectant 0% to1% Surfactant 0% to 10% Cross-linker 0% to 1% Dispersant 0% to 10%

Modulation of Release of Drug

As previously discussed, the combination of the layers and components ofthe coating of the present invention serve to modulate the release of atleast one drug from the coating, first from the drug reservoir layerinto the barrier layer, and from the barrier layer to outside thebarrier layer.

A variety of physical and chemical forces influence the modulation ofthe release of a drug from a coating of the present invention. Theseinclude, but are not limited to diffusion characteristics of at leastone layer of a coating of the present invention or the coating itself,capillary action characteristics of at least one layer of a coating ofthe present invention or the coating itself, mass action characteristicsof at least one layer of a coating of the present invention or thecoating itself, concentration gradient of a drug in at least one layerof a coating of the present invention or the coating itself, solubilityof a drug characteristics of at least one layer in a coating of thepresent invention or the coating itself, temperature, molecular weightof a drug, size of a drug, encapsulation structures for a drug,thickness of at least one layer of a coating of the present invention orthe coating itself, porosity of at least one layer of a coating of thepresent invention or the coating itself, the pore size of at least onelayer of a coating of the present invention or the coating itself, themolecular exclusion size or characteristics of at least one layer of acoating of the present invention or the coating itself, the watercontent of at least one layer of the coating of the present invention orthe coating itself, the concentration of a drug in at least one layer ofa coating of the present invention or the coating itself, theconcentration gradient of a drug in at least one layer of a coating ofthe present invention or the coating itself, and the packagingenvironment presented to the coating of the present invention.

In one aspect of the present invention, the at least one drug hassustained release over time. This aspect of the present invention isdescribed in further detail in Example 9 herein. In another aspect ofthe present invention, the at least one drug has intermittent releaseover time. This aspect of the present invention is described in furtherdetail in Example #9 herein. In yet another aspect of the presentinvention, more than one drug is released at a time. This aspect of thepresent invention is described in further detail in Example 9 herein.

Contact Lens

In one preferred aspect of the present invention, the medical devicehaving a coating being made includes a contact lens. Contact lenses thatinclude a drug, on the surface of the contact lens or within the contactlens are known in the art. However, these contact lenses do not providethe structures of the present invention, such as the at least onecoating that includes at least one drug reservoir layer that can includeat least one drug, and at least one barrier layer that can includestructures, wherein the release of the at least one drug from the atleast one coating layer is modulated by at least one layer of thecoating of the present, either alone or in combination.

The choice of printing technologies used to make the various layers ofthe coating of the present invention, including the coating layer as awhole, is a choice for the artisan based on the state of the art and theteachings provided herein, as well as an evaluation of the variousfactors to consider when choosing a printing technology to produce astructure having desired chemical and physical properties, along with aconsideration of the printing formation to be used.

A variety of materials are known in the art for making contact lensesand are useful in the present invention. Preferred materials include,but are not limited to, acrylics, silicones, polyvinylalcohols, andcombinations thereof. These materials are provided on the surface of thecontact lens to be modified using the methods of the present invention.

There are a variety of general types of contact lenses known in the artand are useful in the present invention. Preferred general types ofcontact lenses include, but are not limited to hybrid lenses,hydrophilic lenses and hydrophilic lenses. These types of contact lensesprovide a surface of the contact lens to be modified using the methodsof the present invention.

In addition, there are other general types of contact lenses known inthe art and are useful in the present invention. These lenses include,but are not limited to spherical lenses, toric lenses, multifocallenses, tinted lenses, corrective optical power lenses and lenseswithout corrective optical power. These types of contact lenses providea surface of the contact lens to be modified using the methods of thepresent invention

There are a variety of methods used to make lenses that are useful inthe present invention. Preferred methods of making, at least in part orin combination, contact lenses include, but are not limited to, lathing,cast molding, spin casting and ink jet printing. These contact lensesprovide a surface of the contact lens to be modified using the methodsof the present invention

Once a contact lens is manufactured, a variety of secondary or finishingoperations can be utilized and are useful in the present invention.Preferred secondary or finishing operations include, but are not limitedto edging, polishing, tinting, hydration, extraction, and sterilization.These secondary or finishing operations can optionally take place beforeor after the contact lens is modified by a method of the presentinvention, or both.

In one aspect of the present invention, the at least one drug in an atleast one coating layer can be provided on the surface of a contactlens. In another aspect of the present invention, the at least one drugin at least one coating layer can be provided within a contact lens. Inanother aspect of the present invention, the at least one drug can beprovided inside a contact lens without the structures in an at least onecoating layer in combination with at least one drug in at least onecoating layer on the surface of a lens. In yet another aspect of thepresent invention, the at least one coating layer with at least one drugcan be provided both on the surface of the lens and inside the lens.

In some cases, drugs provided within the at least one coating can haveoptical properties that can interfere with the optical function of thecontact lens, such as drugs having coloring or opaqueness. Preferreddrugs for use in the present invention do not have such opticalproperties, but that need not be the case as drugs having such opticalproperties are useful in the present invention.

In another aspect of the present invention, the one or more coatings canoptionally dispersed therein nanoparticles having a particles size lessthan about 50 nm, a nanoencapsulated ophthalmic drug from which theophthalmic drug is able to diffuse into and migration through thecontact lens and into the post-lens tear film or towards the eyelid whenthe contact lens is placed on the eye, the nanoparticles being dispersewithin the contact lens or on at least one surface of the contact lensin an amount such that the lens optionally remains substantiallyoptically transparent (see, for example, U.S. Pat. No. 7,638,137B2 toChauhan et al., issued Dec. 29, 2009).

In another aspect of the present invention, the one or more coatings canoptionally dispersed therein nanoparticles having a particles size lessthan about 50 nm, a nanoencapsulated ophthalmic drug from which theophthalmic drug is able to diffuse away from and migrate away from thecontact lens and into the post-lens tear film or towards the eyelid whenthe contact lens is placed on the eye, the nanoparticles being dispersewithin the contact lens or on at least one surface of the contact lensin an amount such that the lens optionally remains substantiallyoptically transparent (see, for example, U.S. Pat. No. 7,638,137B2 toChauhan et al., issued Dec. 29, 2009).

In yet another aspect of the present invention, when the at least onedrug is provided with or without a drug delivery compositions asdescribed herein, the at least one drug as provided with or without adrug delivery compositions is substantially optically transparent.However, this need not be the case. In one aspect of the presentinvention, when the at least one drug as provided with or without a drugdelivery composition is substantially optically transparent or is notsubstantially optically transparent, the optical characteristics of theat least one drug, or other structures of the at least one coatinglayer, can be masked with opaque material or tinting, such as colortinting as is known in the art.

Packaging

An article of manufacture made by a method of the present invention canbe provided in a variety for forms and packaging formats and solutionsas present. Many of these packaging form and formats are establishedpackaging formats, whereas others are unique to the present invention.

The article of manufacture made by a method of the present invention canbe provided in a packaging in a dry state, preferably in a dehydratedstate or a lyophilized state using methods know in the art. The articleof manufacture made by a method of the present invention can also beprovided in a packaging in a wet state, that is to say provided in anappropriate solution and, as appropriate, in a hydrated state.

The format of the packaging can be any as is appropriate. For example,the article of manufacture made by a method of the present invention canbe provided in packaging that is appropriate and normal for the articleof manufacture, such as vials, other containers such as boxes or plasticcontainers, or in vials. Vials and blister packaging are preferable, butnot necessary, for example, for contact lenses.

The solution present, if any, in a packaging format, in particular for awet state packaging format can include the at least one drug present inthe at least one coating layer, a different drug that that provided inthe coating layer, or a combination thereof.

In one instance, the concentration of the drug in a packaging solutionis less than the concentration of the drug in the coating layer. In thatcase, it is likely that the drug in the coating layer may migrate fromthe coating layer into the packaging layer and eventually reach a steadystate equilibrium state, but that not be the case.

In another instance, the concentration of the drug in a packagingsolution is equal to the concentration of the drug in the coating layer.In that case, it is likely that the drug in the packaging solution willbe in steady state with the drug in the coating layer, but that need notbe the case.

In the alternative, the concentration of the drug in the packagingsolution is greater than the concentration of the drug in the coatinglayer. In that case, it is likely that the drug in the packagingsolution would migrate into the coating layer and eventually reach asteady state equilibrium state, but that need not be the case.

In yet another instance, a drug provided in the packaging layer that isnot present in the coating layer may be present. In that case, it islikely that the drug in the packaging solution would migrate into thecontact lens and eventually reach a steady state equilibrium state, butthat need not be the case.

III Methods of Using Lenses Including a Medicament

The present invention includes method of treating or preventing adisease, disorder or condition or condition including: a) providing asubject in need of treatment of said disease, disorder or condition; andb) providing the subject the article of manufacture of the presentinvention, optionally made using the methods of the present invention,at a location appropriate for the treatment of said disease, disorder orcondition; wherein the article of manufacture releases the one or moredrugs in an amount sufficient to treat or prevent said disease, disorderor condition.

The article of manufacture of the present invention, its components anda compositions along with their desirable characteristics and selectioncriteria, how they are arranged and function together, and what criteriacan be utilized to select and arrange them for a particular article ofmanufacture for a particular purpose, have been described herein. Inaddition, the methods of manufacture of the article of manufacture ofthe present invention, along with the manufacture of the coating layerand its various components, including but not limited to the drugreservoir layer, the drug receiving layer, and the barrier layer andstructures provided therein, along with the printing formulations andprinting technologies used to make them and the physical characteristicsof the modulation of drug release therefrom, along with the criteria forselecting them for the manufacture of an article of manufacture for aparticular purpose have also been described herein. The criteria for theselection of a drug, including for what purpose it is to be used for,its physical characteristics, its concentration, release characteristicsand modulation thereof, have also been described herein.

An article of manufacture of the present invention, optionally made by amethod of the present invention, tailored for the treatment orprevention of a particular disease, disorder or condition, and the drughas been selected and provided for in the article of manufacture suchthat the release characteristics have been evaluated based on thedesired dose, regime, route of administration and locus ofadministration, and the pharmacological characteristics of the drug isprovided. The drug has preferably been selected to match the disease,disorder or condition at hand, along with the locus at which it isreleased based on the criteria disclosed herein and provided by thestate of the art.

A subject in need of treatment or prevention of a disease disorder orcondition is also provided. The article of manufacture is then place onor within the subject at a desirable location using methods known in theart based on the locus at which the article of manufacture of thepresent invention is place (such as, but not limited, insertion on asurface, insertion, or implantation, inclusive of surgery if called for)such that the drug is released from the article of manufacture to treator prevent a disease, disorder or condition. When the drug has beenreleased over time, the article of manufacture can be removed from thesubject, or in the alternative, removed from the subject. In the case ofan article of manufacture of the present invention that has been placedon readily accessible locus of a subject, such as the skin or eye, theremoval is readily performed. In the case of articles of manufacture ofthe present invention that have been implanted or inserted into asubject, the removal process is more complex and may require surgery. Insome instances, removal of an article of manufacture of the presentinvention from a subject is not desirable due to the discomfort or riskassociated with the removal. In that instance, the article ofmanufacture can remain in place.

EXAMPLES Example #1

Preparation of Printable Formulation Using a Hydrophilic Drug

This example provides printable formulation with a drug used to inkjetprint lenses.

The printable formulation include a base formulation that include thefollowing: monomer (HEMA), initiator (BME), crosslinker (EGDMA), drug#1, diluent (glycerine), solvent (isopropanol), optional drug #2,dispersant (polyvinyl alcohol), humectant (ethylene glycol), co-monomer(methacrylic acid); inhibitor (MEHQ), antikogating agent (methylpropanediol), and antioxidant (alkylated hydroquinone). Theconcentration of these constituents are as appropriate for making a lensof desired characteristics and physical properties. Drug #1 and optionaldrug #2 can be any drug or combination of drugs to provide a desiredactivity.

A preferred monomer mixture for making a clear lenses coating has thefollowing formulation: monomer (HEMA), monomer (EOEMA), monomer (MAA),crosslinker (EGDMA), initiator (Vazo-64), inhibitor (MEHQ) and diluent(glycerine). The concentration of these constituents are as appropriatefor making a lens of desired characteristics and physical properties.

When drugs are used in jet printing devices, the drug is preferablywater based or monomer based (U.S. Pat. No. 5,658,376). The drug ispreferably soluble in water and an organic solvent and preferablyincludes a dispersant. A water soluble polymer such as polyvinyl alcoholand a dispersant such as polyvinylpyrrolidone are-preferred. Asurfactant is preferably provided, such as polyoxyethylene alkyl etheror polyoxyethylene alkylphenyl ether having an aminic acid group. Theprintable preferably includes a surfactant, such as between about 0.3%and about 1% by weight. The PF preferably includes an antiseptic agentsuch as Proxel (Zeneca, U.K.). The printable formulation preferably hasa pH of between about 7 and about 10 and a viscosity at about 25 C ofbetween about 1 to 50 cps. Antioxidants, such as low corrosion orantioxidant agents, such as alkylated hydroquinone can also be included,preferably between about 0.1% and about 0.5% by weight (U.S. Pat. No.5,389,132). A printable formulation can also include a humectant such as1,3-dioxane-5,5-dimethanol, 2-methyl-1,3-propane diol, ethylene glycolor diethylene glycol. When used in printing, the driving frequency ispreferably between about 3 kHz and about 8 kHz (see generally, U.S. Pat.No. 5,658,376). Preferred printable formulation properties include asurface tension of between about 20 dynes/cm and about 70 dynes/cm and aviscosity between about 1.0 cp and about 2.0 cp (U.S. Pat. No.5,271,765).

Example #2

Solvent Soluble Drug

This example provides a printing formulation with a solvent soluble drugused to inkjet print lenses.

A preferable formulation with a solvent soluble drug has the followingcomposition and physical properties.

Materials Material Type DI Water Solvent Glycerin Solvent 1,3-propandiolSolvent Water Soluble Drug Drug Surfynol CT 121 Surfactant TriethylAmine 10% in water Additive

-   Viscosity=3.5 centipoise, UL, 60 rpm, 25° C.-   Surface tension=32 dynes/cm;-   pH=8.4.-   The formulation was filtered through 0.45 micron Nylon filter    membrane.-   Water=Main vehicle, carrier-   Glycerin, 1,3-propandiol=co-solvents-   Surfynol CT121 and 10% TEA solution=additive

The printable formation can also include a drug in encapsulated form.There are several methods available for encapsulation to meet theproduct performance requirements. These methods can be divided into 2broad categories: (see, for example, Southwest Research Institute((SWRI) website, www.microencapsulation.swri.com), an outline summary ofwhich follows:

1.) Preferred physical methods of encapsulation include, but are notlimited to:

-   -   Extrusion    -   Fluidized bed    -   Pan coating    -   Atomization,    -   Spinning Disk    -   Spray Drying    -   Spray Chilling/Congealing    -   SphereJet by Microfab

2.) Preferred chemical methods of encapsulation include but are notlimited to:

-   -   Solvent loss    -   Phase separation    -   Coacervation    -   Polymerization    -   Precipitation    -   Nanoencapsulation    -   Liposomes    -   Sol-gel

These methods and related technologies are well documented in literatureand is incorporated in this patent. (see, for example“MICROENCAPSULATION TECHNIQUES, FACTORS INFLUENCING ENCAPSULATIONEFFICIENCY: A REVIEW” by N. V. N. Jyothi; Suhas Narayan Sakarkar; G. Y.Srawan Kumar; Muthu Prasanna. Source: journal of microencapsulation,Informa Health Care, Volume 27, Issue 3, p. 187-197)

In addition, Chauhan et al. in U.S. Pat. No. 7,638,137 B2, provides adetailed list of various types of nanoparticles, including silica usedfor encapsulating drugs. (see, for example, page 5, lines 9 through 80).Chauhan et al. also discusses different types of micro-emulsions andmethods used to prepare them. Chauhan et al. also provides details ofdrug release studies carried out with a micro- or nano-encapsulatedocular drug, Lidocaine, when embedded inside the lens while the presentinvention has a novel approach of incorporation the drug on the surfaceof the lens rather than inside the lens. Many of the aspect for drugrelease are essentially the same (see, for example, U.S. Pat. No.7,638,137 B2).

The following is an example of a printable formulation for a micro- ornano-encapsulated hydrophobic ocular drug such as Timolol that may beincorporated in a printable formulation that uses a derivatized oligomerof HEMA to provide dimensional stability and good adhesion when thefinished, hydrated lens may be sterilized multiple times.

Example #3

Preparation of an Oligomer Capable of Free Radical Polymerization forUse in Printable Formulations

A Poly hydroxy ethyl methacrylate prepolymer is prepared according tothe following procedure. The following components are mixed:

Material % Methacrylic acid 0.82% Mercaptoethanol 0.70% Allylmethacrylate 0.16% Ethyl triglycol methacrylate 3.50% N-Vinylpyrrolidinone 6.07% 2-Hydrozyethyl methacrylate 35.42% Vazo 64 0.33%1-Ethoxy-2-propanol 44.80% 1-Methoxy-2-proply acetate 8.21%

Thermal polymerization is carried out in a steel can fitted with an overhead stirrer and mounted on a hot plate. The mixture is heated andtemperature of the mixture is maintained at about 85° C. to about 90° C.by moving the can/stirrer assembly between cold water bath and the hotplate as necessary. The reaction is allowed to continue for about 37minutes from initially reaching 85° C. prior to quenching polymerizationby placing the can/stirrer assembly into the cold water bath. The coldprepolymer viscosity is checked and stored in a refrigerator. A typicalviscosity of the prepolymer is about 2000 cp to about 3000 cp.

To a solution of 20 grams of the Polyhydroxy ethyl methacrylateprepolymer with a viscosity of 2000 to 3000 cP in solvent1-methoxy-2-propanol is added 0.2 grams of triethyl amine and stirredwell with a magnetic stir bar for 30 minutes. 2 grams of methacryloylchloride solution, 10% in 1-methoxy-2-propanol, is added while stirringat room temperature. The reaction mixture is stirred overnight thuscreating a prepolymer derivative, or an alpha beta unsaturated oligomer.

It is noted that derivatized oligomer for polyvinyl alcohol, glycidolmethacrylate, silicone, n-n-dimethylacrylamide can be prepared similarlyto facilitate free radical polymerization with these polymers.

Example #4

Printable Formulation for Ink-Jet Printing a Drug Reservoir with Drug

The amount of the alpha beta unsaturated oligomer, or prepolymerderivative, provided in Example 2 and 2-hydroxyethyl methacrylate (HEMA)are prepared for comparison according to the following table:

Sample Printable Formulation Components % Range (%) Prepolymerderivative from Example # 2 20 5-15 Encapsulated drug like Timolol forGlaucoma in 8 0.001-25    HEMA: PEG 400 diacrylate: 5 0-10N-vinyl-2-pyrrolidone monomer hydrogel: 26 0-99 Glycerol methacrylatemonomer hydrogel: 13.3 0-99 2-hydroxyethyl methacrylate monomerhydrogel: 32.7 0-99 Photoinitiator (Irgacure 1800): 3.5 0-10Photoinitiator (Irgacure 819): 1.5 0-10 Total 100 —

The viscosity and surface tension of the printable formulations aremeasured and the results are as follows:

Actual Range Viscosity (cp) 15.4  5-50 Surface Tension (dynes/cm) 38.120-70 It is noted here that: 1.) Removal of drug from the PF Example # 3can provide printable formulation for an inkjet printed barrier layer.2.) Barrier layers of different polymers can be also made by usingderivatized oligomer of pertinent polymer.

Example #5

Use of a Printable Formulation for Pad-Transfer Printing Drug ReceivingLayer

A printable including an oligomer capable of free radical polymerizationcan also be used with pad-transfer printing. Printable formulations ofthe present invention for use with a pad-transfer printing technique canbe provided at a viscosity form about 5,000 cp to about 50,000 cp.Printable formulations can be adjusted to a higher viscosity bysubstituting a relatively low molecular weight oligomer as providedherein with an oligomer having a higher molecular weight such as onethat results in a polymer from about 20,000 cp to about 50,000 cp. Theviscosity can be further adjusted by the addition of polymers ormonomers or surfactants.

Pad-transfer printing of a layer may include dispersing the printableformulation having a viscosity from about 5,000 to about 50,000 on amold or a cliche, dipping a substrate or polymer in the solution andcuring the resulting drug reservoir on substrate or polymer. The curing,hydration and sterilization process may be the same as those previouslydisclosed in the ink-jet printing examples and as described herein.

An example of such a printable formulation is provided below.

Prepolymer formula For a Pad Printed Receiving Layer Ingredient % Range(%) HEMA 26.7%  0.5-90 NVP 14.4%   5-40 Allyl Methacrylate 0.4% 0.1-22-Mercaptoethanol 1.3% 0.1-2 MAA 0.8% 0.1-4 Vazo 64 0.3% 0.1-2 Ethyltriglycol methacrylate 3.5% 0.1-5 1-Ethoxy-2-propanol 44.4%  10-801-Methoxy-2-propyl acetate 8.1%   2-30 Total 100.0% — Visc~5000 cp

Pad Print Formulation Ingredient % Range (%) Pre-polymer from Above0.893 0.1-10 Hardener (Blocked HDI) 0.107 0.1-2  Total 100.0%

When the above printable formulation is cured in vacuum oven at 140° C.for about 1 hour it provides the drug receiving layer for a solventsoluble drug.

Example #6

Printing Methods for Use with Printable Formulations

One advantage of present invention is to print structures of the surfaceof a medical device, such as a lens, not only to achieve desired drugrelease rate but also offer flexibility of incorporating multiple drugsfor multiple treatments, intermittent drug release, consistent drugrelease of zero order kinetics, uni-directional drug release, etc.without optical interference. Such structures can be printed usingvarious printing techniques that include, but are not limited to, inkjetprinting, piezo printing, thermal printing, laser printing, pad transferprinting, impregnation, photolithography, silk screen printing,micro-dispensing material deposition system, SLA stereolithographysystems, 3D printers, etc. Some advantages of such printing are thatthis additive manufacturing technology offers include, but are notlimited to material savings, mass customization, high precisionautomation friendly system (see, for example, The Economist: 3Dprinting: The printed world: Three-dimensional printing from digitaldesigns will transform manufacturing and allow more people to startmaking things. Feb. 10th 2011, FILTON, from the print edition).

Printing of such structures, preferably carried out with digitalprinters (inkjet printing or laser printing, for example) essentiallyuses inherent advantages of digital printing, that includes, but notlimited to, drop on demand with a preferable volume of less than 5picoliter to 500 picoliter, with more than 2400 dpi, and with highspeed, more than 500 sq. ft./hr, which are characteristics or featuresof inkjet printers. The following is a list of printers, including butnot limited to, printers currently used for constructing 3D structuresare given below. Some of these printers have position accuracy of +/−2.5micron and repeatability of +/−1 micron at present. Incorporated hereinare such printers, available now or such printers with better accuracy,precision, repeatability, quality, and the like, which may or will beavailable at a later date.

In addition to these types of 3D printers, currently available highprecision, high speed, high resolution, wide format, piezo printers,thermal printers, laser printers can be modified to digital print layerby layer the structures of the present invention.

Example #7

Inkjet Printing of 3D Structures

A. Inkjet Printable Formulations in Cartridge

In a simplified version of such printers with multiple cartridges willhave the following printable formulations in different cartridges

1.) Drug receiving layer

2.) Drug Reservoir with drug

3.) Soluble drug formulation

4.) Barrier layer A formulation

5.) Barrier layer B formulation

6.) Barrier layer C formulation

For multiple drug system additional cartridge may be incorporated orexisting cartridge may be substituted for additional drugs.

B. Digital Storage of 3D Structure

Using appropriate software like SolidWorks, a 3D drawing of desiredstructure is digitally stored in a computer.

The computer software for a 3D printer would divide such 3D structuresin multiples of layer by layer coatings.

C. Inkjet Printing:

Such layer coatings are then inkjet printed sequentially, cured, fusedusing appropriate curing/fusing process to build the desired 3Dstructures.

Thickness of layer (inclusive of a drug reservoir layer, a drugreceiving layer, a barrier layer or a combination thereof) can bepreferably be controlled to about or less than 0.1 micron to about orless than 10 micron using preferable drop volume of less than about 1picoliter to less than about 100 picoliters.

Examples of Inkjet printers, included but not limited to, that may beused are given earlier. In addition many commercially available flat bedwide format printers, like Mimaki JF 1610 and 1631 or HP DesignjetH45000 printer series, that are high speed, high precision, can also bemodified and used for the applications of the present invention. Suchprinters may use piezo printerhead like Spectra Polaris PQ512/15 AAA orgray scale, drop on demand printing system along with simultaneous UVcure system (Xennia XJ-4000) or thermal cure system.

Example #8

Modulation of Drug Release Rate

Generally the drug release rate can be modulated through one or more ofthe following factors available to one with understanding of the art.

1.) Creation of different barrier layers with different diffusivity,different thickness

2.) Different drug concentration at different heights, locations andsurface area.

3.) Different sizes of nano- or micro-encapsulated drug

The present invention also offers creation of capillaries of differentdiameter or different height to provide additional tool for modulatingdrug release rate.

The Lucas-Washburn equation that predicts the rise of the fluidmeniscus, H(t), in the capillary with time t is given as:H(t)=[(sR cos {acute over (Ø)}/2n)½t½

Where:s=fluid surface tension

-   -   n=fluid shear viscosity    -   R=pore radius    -   {acute over (Ø)}=contact angle between meniscus and wall        (Ref. D. I. Dimitrov 1, A. Milchev 1,2, and K. Binder, Institut        fúr Physik, Johannes Gutenberg Universität Mainz, Staudinger Weg        7, 55099 Mainz, Germany

-   2Institute for Chemical Physics, Bulgarian Academy of Sciences, 1113    Sofia, Bulgaria, Received 30 Mar. 2007; published 31 Jul. 2007).

One can use this equation to determine the drug release rate,R_(capillary), for a capillary of given height, diameter, contact angle,viscosity and surface tension. The diameter and height of capillariescan be at the nanometer level, for example, they can be less than 5nanometers to 50,000 nanometers.

Example #9

Modulation of Drug Release Rate Using a Combination of Factors

Referring to FIG. 10 and FIG. 11, it can be observed that drug releaserate may be modulated by changing orientation of the barrier layers A, Band C.

Thus for FIG. 10, where the barrier layer A, B and C are on top of eachother, the drug release rate R is:R _(drug) =R _(a) ×R _(b) ×R _(c)  (I)

Whereas for FIG. 11, for the same drug and same barrier layers, one canmodulate drug release rate, significantly just by constructing thebarrier layers A, B and C next to each other. The drug release rate inthat case now becomesR _(drug) =R _(a) +R _(b) +R _(c)  (II)

This drug release rate can further be modified by printing structureswith capillaries as shown in FIG. 12. The drug release rate is nowmodulated to:R _(drug) =R _(a) +R _(b) +R _(c) +R _(capillaries)  (III)

Equation I, II, and III suggests ability to modulate the drug releaserate through constructing a three dimensional structure with differentbarrier materials, controlling thickness and orientation of barrierlayer, providing additional structure of capillaries, adjusting drugconcentration (by printing number of drops, size of drops, location ofdrops etc.) it will be possible to get the desired drug release ratesincluding but not limited to zero order kinetics i.e. sustained drugrelease rate.

Additionally it may be observed from FIG. 8, for multiple drugs, how twodifferent drugs can be delivered at different rate from the lens surfaceby locating drugs in different area with different barrier layers chosento provide the desired drug release rate for each drug.

Similarly, by referring to FIG. 4, where drug reservoir layers ofdifferent surface area are created at different height from the lenssurface, as well as capillaries of different heights and diameters arecreated; can be used to provide intermittent drug release. For example,let's say that all the drug from the top reservoir is released in thefirst two hours. The barrier layers and capillary height from reservoir2 is constructed such a way that it will take drug 4 hours to reach thetop of the lens surface.

Example #10

Lens Finishing

The contact lens surface on which the 3 D structure is created can betreated with proper edging/polishing process to help assure lens wearcomfort. These lenses then can be hydrated, extracted, and inspected.Packaged and sterilized. The packaging can be with dry lens wheresolution is provided separately to hydrate the lens before use. Theconventional wet packaging in a vial or blister pack may be done in sucha way as not to affect drug release rate in the eye, when in use, bycontrolling the concentration of drug in packaging environment or suchsimilar way. Also, the barrier layer, drug receiving layer and drugreservoir layer are formulated such that they swell the same orsubstantially the same as the substrate lens so that it does notsubstantially affect lens dimensions.

All publications, including patent documents and scientific articles,referred to in this application and the bibliography and attachments areincorporated by reference in their entirety for all purposes to the sameextent as if each individual publication were individually incorporatedby reference.

All headings are for the convenience of the reader and should not beused to limit the meaning of the text that follows the heading, unlessso specified.

What is claimed is:
 1. A drug delivery contact lens, comprising: a) acontact lens comprising a first surface and a second surface; and b)said contact lens further comprising at least one coating provided on atleast a portion of said first surface, said second surface, or acombination thereof as opposed to within said contact lens; 1) saidcoating comprising at least one three dimensional structure; and 2) saidthree dimensional structure comprising: a. one or more drug reservoirlayers; wherein said one or more drug reservoir layers comprise one ormore drugs; and b. one or more barrier layers; wherein said one or morebarrier layers modulate the release of said one or more drugs from saiddrug delivery contact lens; wherein said one or more drug reservoirlayers, said one or more barrier layers, or a combination thereof, areoriented vertically, horizontally, or a combination thereof, relative toeach other.
 2. The drug delivery contact lens of claim 1, wherein saiddrug delivery contact lens is stored in a hydrated form.
 3. The drugdelivery contact lens of claim 1, wherein said drug delivery contactlens is stored in a solution comprising said one or more drugs.
 4. Thedrug delivery contact lens of claim 1, wherein at least a portion ofsaid contact lens is a not physically modified, complete, solid, drypre-formed contact lens or a dry pre-made contact lens.
 5. The drugdelivery contact lens of claim 1, wherein said first surface, saidsecond surface, or a combination thereof of a contact lens is a smoothsurface.
 6. The drug delivery contact lens of claim 1, wherein said drugdelivery contact lens is not biodegradable.
 7. The drug delivery contactlens of claim 1, comprising one or more drug reservoir layers and one ormore barrier layers, the layers positioned such that: at least onebarrier layer is adjacent to at least one drug reservoir layer in avertical or horizontal arrangement.
 8. The drug delivery contact lens ofclaim 1, comprising one or more drug reservoir layers and one or morebarrier layers, the layers positioned such that: at least one barrierlayer is distal to at least one drug reservoir layer, or at least onedrug reservoir layer is positioned distal to at least one barrier layer,relative to an outer surface of the lens, or a combination thereof. 9.The drug delivery contact lens of claim 1, comprising one or more drugreservoir layers and one or more barrier layers, the layers positionedsuch that: an outer surface of the lens is positioned below at least onedrug reservoir layer, and at least one drug reservoir layer ispositioned below at least one barrier layer.
 10. The drug deliverycontact lens of claim 1, comprising one or more drug reservoir layersand one or more barrier layers, the layers positioned such that: one ormore barrier layers made of the same or different material compositions,being positioned horizontally and directly adjacent relative to eachother and above one or more drug reservoir layers.
 11. The drug deliverycontact lens of claim 1, comprising one or more drug reservoir layersand one or more barrier layers, the layers positioned such that: two ormore barrier layers, each barrier layer made of one or two or moredifferent materials compositions being positioned side by side withoutintervening spaces between the barrier layers and directly on andperpendicular to a drug reservoir layer, wherein an outer surface of alens is positioned below a drug reservoir layer.
 12. The drug deliverycontact lens of claim 1, comprising one or more drug reservoir layersand one or more barrier layers, the layers positioned such that: two ormore barrier layers, each made of the same or different materialcomposition, when made of different material compositions each barrierlayer made of one of two or more different material compositions, beingpositioned side by side with intervening spaces between the barrierlayers and directly on and perpendicular to a drug reservoir layer,wherein an outer surface of a lens is positioned below a drug reservoirlayer.
 13. The drug delivery contact lens of claim 1, wherein saidcontact lens comprises the not biodegradable material polyHEMA, polyGMA,polyvinylacohol, polyDMA, PMMA (polymethylacrylicacid), PVP(polyvinylpyrolidone), silioxane, or a combination thereof.
 14. The drugdelivery contact lens of claim 1, wherein said contact lens is made bylathing, cast molding, spin casting, ink jet printing, or a combinationthereof before said coating is applied.
 15. The drug delivery contactlens of claim 1, wherein said contact lens is made by cast molding, spincasting, or a combination thereof before said coating is applied. 16.The drug delivery contact lens of claim 1, wherein optical properties ofat least a portion of said lens with said coating are unchanged fromsaid contact lens.
 17. The drug delivery contact lens of claim 1,wherein said first surface, said second surface, or a combinationthereof of said contact lens is polished prior to application of saidone or more three dimensional structures.
 18. The drug delivery contactlens of claim 1, wherein said first surface, said second surface, or acombination thereof of said contact lens has not been subject to afinishing operation prior to application of said one or more threedimensional structures.
 19. The drug delivery contact lens of claim 1,wherein said first surface, said second surface, or a combinationthereof of said contact lens does not comprise etching or scorings of atleast a portion of said lens prior to application of said one or morethree dimensional structures.
 20. The drug delivery contact lens ofclaim 1, wherein at least a portion of said first surface, said secondsurface, or a combination thereof of said contact lens is unmodifiedprior to application of said one or more three dimensional structures.21. The drug delivery contact lens of claim 1, wherein at least aportion of said three dimensional structure is not biodegradable. 22.The drug delivery contact lens of claim 21, wherein said threedimensional structure comprises in whole or in part at least onepolymer, at least one plastic, at least one partially polymerizedpolymer, at least one polymer matrix, at least one protein matrix, atleast one silicone, or a combination thereof.
 23. The drug deliverycontact lens of claim 1, wherein said three dimensional structurecomprise the not biodegradable material polyHEMA, polyGMA,polyvinylacohol, polyDMA, PMMA (polymethylacrylicacid), PVP(polyvinylpyrolidone), silioxane, or a combination thereof.
 24. The drugdelivery contact lens of claim 1, wherein said three dimensionalstructure does not release said at least one drug by way ofbiodegradation.
 25. The drug delivery contact lens of claim 1, whereinsaid three dimensional structure does not comprise capillary structures.26. The drug delivery contact lens of claim 1, wherein said threedimensional structure comprises capillary structures.
 27. The drugdelivery contact lens of claim 1, wherein said three dimensionalstructure has a shape that corresponds to or approximates that of theeye of a subject.
 28. The drug delivery contact lens of claim 1, whereinsaid drug reservoir layer is not biodegradable.
 29. The drug deliverycontact lens of claim 28, wherein said drug reservoir layer comprises inwhole or in part at least one polymer, at least one plastic, at leastone partially polymerized polymer, at least one polymer matrix, at leastone protein matrix, at least one silicone, or a combination thereof. 30.The drug delivery contact lens of claim 1, wherein said drug reservoirlayer comprise the not biodegradable material polyHEMA, polyGMA,polyvinylacohol, polyDMA, PMMA (polymethylacrylicacid), PVP(polyvinylpyrolidone), silioxane, or a combination thereof.
 31. The drugdelivery contact lens of claim 1, wherein said drug reservoir layer isat least in part printed by printing other than additive digital threedimensional printing.
 32. The drug delivery contact lens of claim 31,wherein said printing other than additive digital three dimensionalprinting comprises at least one pad printing, at least one MEMSprinting, at least one coating printing, at least one soaking printing,at least one impregnation printing, at least one spin coating printing,at least one drip coating printing, at least one screen coatingprinting, at least one silk screen coating printing, or a combinationthereof.
 33. The drug delivery contact lens of claim 1, wherein saiddrug reservoir layer does not comprise capillary structures.
 34. Thedrug delivery contact lens of claim 1, wherein said barrier layer is notbiodegradable.
 35. The drug delivery contact lens of claim 34, whereinsaid barrier layer comprises at least one polymer, at least onepartially polymerized polymer, at least one polymer matrix, at least oneprotein matrix, at least one silicone, at least one ceramic, at leastone glass, at least one carbon compound, at least one fabric, or acombination thereof.
 36. The drug delivery contact lens of claim 1,wherein said barrier layer comprises the non-biodegradable materialpolyHEMA, polyGMA, polyvinylacohol, polyDMA, PMMA(polymethylacrylicacid), PVP (polyvinylpyrolidone), silioxane, or acombination thereof.
 37. The drug delivery contact lens of claim 34,wherein at least a portion of said barrier layer does not release saidat least one drug by way of biodegradation.
 38. The drug deliverycontact lens of claim 1, wherein said drug comprises at least one smallmolecule drug, at least one biological drug, at least one encapsulateddrug, at least one nanoparticle, at least one dispersed drug, or acombination thereof.
 39. The drug delivery contact lens of claim 38,wherein said biological drug comprising at least one protein comprisesat least one enzyme, at least one transport protein, at least onestructural protein, at least one storage protein, at least one hormoneprotein, at least one receptor protein, at least one contractileprotein, at least one antibody, at least one monoclonal antibody, or acombination thereof.
 40. The drug delivery contact lens of claim 1,wherein optical properties of at least a portion of said lens with saidcoating is unchanged from said contact lens, wherein said coatingcomprises one or more drugs.
 41. The drug delivery contact lens of claim1, wherein the structure and/or composition of said one or more drugreservoir layers and/or said one or more barrier layers results in therelease of the one or more drugs simultaneously, or at different times,or over an extended period of time, or a combination thereof.
 42. Thedrug delivery contact lens of claim 1, wherein said one or more drugsare released from said three dimensional structure in zero-orderkinetics or other than in zero order kinetics.
 43. The drug deliverycontact lens of claim 1, wherein said one or more drugs are releasedfrom said three dimensional structure in sustained release.
 44. The drugdelivery contact lens of claim 1, wherein the one or more drugs releasedfrom said three-dimensional structure according to one or more kineticorders.
 45. The drug delivery contact lens of claim 1, wherein said oneor more drugs released from said three-dimensional structure atdifferent rates of flux at different times.
 46. The drug deliverycontact lens of claim 1, wherein said barrier layer modulates thedirectional release of said drug away from said drug delivery contactlens.
 47. The drug delivery contact lens of claim 1, wherein saidbarrier layer does not modulate release of said drug from said drugreservoir layer by way of capillary action.
 48. The drug deliverycontact lens of claim 1, wherein said barrier layer modulates therelease of said drug from said drug reservoir layer by the diffusivityof said barrier layer.
 49. The drug delivery contact lens of claim 1,wherein said barrier layer modulates the release of said drug from saiddrug reservoir layer by the thickness of said barrier layer.
 50. Thedrug delivery contact lens of claim 1, wherein said barrier layermodulates the release of said drug from said drug reservoir layer by thesurface area of said barrier layer.
 51. The drug delivery contact lensof claim 1, wherein said barrier layer modulates the release of saiddrug from said drug reservoir layer by the orientation of said barrierlayer.
 52. The drug delivery contact lens of claim 1, wherein saidbarrier layer modulates the release of said drug from said drugreservoir layer by the capillary structures of said barrier layer. 53.The drug delivery contact lens of claim 1, wherein said barrier layermodulates the release of said drug from said drug reservoir layer by theporosity of said barrier layer.
 54. The drug delivery contact lens ofclaim 1, wherein said barrier layer modulates the release of said drugfrom said drug reservoir layer by the molecular exclusion size of saidbarrier layer.
 55. The drug delivery contact lens of claim 1, whereinsaid barrier layer modulates the release of said drug from said drugreservoir layer by the water content of said barrier layer.
 56. The drugdelivery contact lens of claim 1, wherein said barrier layer modulatesthe release of said drug from said drug reservoir layer by the pore sizeof said barrier layer.
 57. The drug delivery contact lens of claim 1,wherein said drug delivery contact lens with the coating is stored in awet packaging environment wherein the concentration of said at least onedrug in the packaging solution is less than, equal to, or greater thanthe concentration of said at least one drug in said at least one drugreservoir layer.
 58. The drug delivery contact lens of claim 1, whereinsaid drug delivery contact lens with the coating is extracted or washedprior to storage in a hydrated form.
 59. The drug delivery contact lensof claim 1, wherein said drug delivery contact lens with the coatingdoes not comprise materials that chemically adhere to the surface of aneye.
 60. The drug delivery contact lens of claim 1, wherein said one ormore drugs are released from said drug delivery contact lens in aneffective amount to treat or prevent a disease, disorder, or conditionof a subject.
 61. The drug delivery contact lens of claim 60, whereinsaid subject is a human subject.
 62. The drug delivery contact lens ofclaim 60, wherein said one or more drugs treat or prevent a disease,disorder, condition of the eye.
 63. The drug delivery contact lens ofclaim 62, wherein said disease, disorder, or condition of the eye thatis treated or prevented is an inflammation, an allergy, an infection,glaucoma, macular degeneration, a parasite, dry eye, eye discomfort, ora combination thereof.
 64. The drug delivery contact lens of claim 62,wherein said disease, disorder, or condition of the eye that is treatedor prevented by a pharmaceutically effective amount of ananti-inflammatory agent, an anti-allergy agent, an anti-infective agent,an antibiotic, an anti-parasitic agent, an anti-glaucoma agent, ananti-macular degeneration agent, an ophthalmic drug, a steroid, ananti-dry eye agent, a comfort agent, or a combination thereof.
 65. Thedrug delivery contact lens of claim 1, wherein said drug deliverycontact lens is hydrated.
 66. The drug delivery contact lens of claim 1,wherein said drug delivery contact lens is not hydrated.
 67. The drugdelivery contact lens of claim 1, wherein said contact lens is hydrated.68. The drug delivery contact lens of claim 1, wherein said contact lensis not hydrated.